Investigating vulnerability to concussion through rare ion channel and neurotransmitter genetic variants

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Symptomatic overlap of post-concussion syndrome with neurological conditions such as familial hemiplegic migraine (FHM) caused by rare pathogenic variants in ion channel and synapse protein genes, and high sensitivity to head trauma for some patients, suggests a role for similar genetic variants in mTBI. In this study we investigated rare protein-altering variants in the known FHM genes, other ion channel or transporters, and genes involved in neurotransmission via whole exome sequencing and analysis of 93 unrelated individuals who had sustained a single or multiple concussions. Some 62 different rare missense variants were identified across 24 genes in 59 participants (63%), with 26 participants harbouring two or more variants. The prevalence of specific likely damaging rare variants in the 16 ion channel-related genes that were identified was ~ 5-fold greater than that observed from gnomAD population controls (Odds Ratio = 5.44, CI: 4.13, 7.18, P < 0.0001). Voltage-gated calcium and sodium channel genes including SCN9A , and specific neurotransmitter-related genes such as SNCAIP , harboured numerous potentially deleterious variants. We suggest such genetic variants may predispose some individuals to be vulnerable to concussion or more severe post-concussion symptoms, precipitated by head trauma. Our results provide important genetic information for further investigation to aid in developing useful biomarkers for understanding concussion risk and prognosis. Molecular Genetics Cellular & Molecular Neuroscience Neurobiology of Disease Concussion genetics ion channels neurotransmitters rare variants traumatic brain injury 1. Introduction Concussion is a condition of neurologic dysfunction resulting from biomechanical forces acting on the brain. Some individuals may be more susceptible to sustaining a concussion or display a range of neurological symptoms of varying severity. While most symptoms are transient and resolve in approximately two weeks, a subset of individuals develop post-concussion syndrome (PCS), experiencing symptoms such as headaches, dizziness, fatigue, and cognitive issues, that persist for months or even years [1-3]. Post-traumatic headache, often meeting the phenotypic criteria for migraine, is one of the most common symptoms following injury [4-6]. Why some people experience concussion with long-term neurological symptoms, and others do not, remains poorly understood. Inter-individual variability may be partly explained by injury severity, age, sex, or pre-injury health; however, there is growing evidence that genetic variation also influences both the likelihood of sustaining a concussion and the trajectory of recovery [7-9]. Previous small-scale genetic studies have investigated the association of concussion risk with genetic variants in genes with known neurological functions, including: Alzheimer’s disease risk APOE E4 allele [10-12] and MAPT [13,14]; BDNF [15,16]; glutamate transporters and receptors SLC17A7 [17] and GRIN2A [18]; and the dopamine receptor gene DRD4 [19]. Genome-wide association studies (GWAS) take a more agnostic approach, ideally with statistically robust sample sizes. In 2021 Kim et al. reported two gene loci with functions in neural development and axon outgrowth ( SPATA5 and PLXNA4 ) significantly associated with concussion risk [20]. A GWAS by Kals et al. that used the extended Glasgow Outcome Scale at 6 months post-TBI as a measure of TBI outcome found 13 genetic loci associated at a suggested level of significance, with several biologically plausible associations such as DOC2A , which is involved in calcium-dependent neurotransmitter release, identified through supplementary transcription-wide association analysis [21]. A large GWAS of TBI in U.S. military veterans in 2024 identified 15 genome-wide significant loci mapping to 14 genes, including APOE , NCAM1 , FOXP2 , and FTO , and found that TBI showed high genetic correlation with psychiatric and risk-taking traits [22]. These studies, with a focus on common genetic variants, support the genetic underpinnings of various aspects of concussion, including the likelihood of sustaining TBI or concussion, recovery profile, and co-occurring symptoms. Studies investigating the mechanisms of TBI indicate that substantial ion fluxes and alterations to neurotransmission occur following injury [23-25]. This is characterised by an efflux of potassium (K + ), alongside the release of excitatory neurotransmitters such as glutamate, and an influx of sodium (Na + ) and calcium (Ca 2+ ) into neurons, which likely result from altered membrane permeability following cellular distortion. These changes promote local and downstream neuronal depolarization through the activation of voltage-gated ion channels of subsequent neurotransmission. Following these acute events, ATP-dependent ion pumps are activated to restore ionic homeostasis. This process substantially increases neuronal energy demand and oxidative stress [23]. The resulting metabolic strain can lead to hyperglycolysis, which is further exacerbated by Ca 2+ -mediated disruption of mitochondrial function. Neuronal energy depletion can last for approximately 2 weeks [26], aligning with the typical recovery period for concussion and highlighting the importance of these early molecular events in its pathophysiology. Changes in the subunit composition of ligand-gated ion channels following a TBI have also been reported in animal models [27-29], and may correlate with the altered cognition and learning displayed by concussion sufferers [30,31]. Thus, neurotransmitters and ion channels are involved in the earliest stages of cellular response to TBI [32], and may represent key players in concurring severity after TBI at the cellular and metabolic level and development of persistent symptoms including post-traumatic headache and migraine. Further evidence of the potential role of genetic variation in concussion and its aftermath arises from the pathophysiological and symptomatic overlap of PCS with other neurological disorders, particularly the ion channelopathies. Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder in which migraine attacks are accompanied by motor dysfunction caused by rare pathogenic variants in ion channel, transporter, and synaptic genes [33]. Some individuals with FHM may have severe responses to trivial head trauma. For example, patients with FHM Type 1 (FHM1) caused by pathogenic variants in the calcium channel gene CACNA1A may exhibit high sensitivity to head impacts; in cases involving the severe p.Ser218Leu mutation, even minor head injury can result in concussion, seizures, cerebral oedema, coma, or death [34,35]. This phenotype closely resembles second-impact syndrome, where a subsequent mild injury following an initial concussion can lead to catastrophic cerebral oedema. FHM1 CACNA1A mutations lead to a gain of Ca V 2.1 channel function with increased Ca 2+ neuronal influx [36]. Knock-in mouse models carrying human CACNA1A mutations display enhanced glutamatergic neurotransmission and an imbalance between excitatory and inhibitory signalling, which facilitates cortical spreading depression (CSD) and worsens outcomes after experimental TBI [37,38]. Importantly, the dysregulated ion fluxes and neurotransmission that occur in FHM mirror the metabolic cascade observed post-TBI and may underlie acute post-concussive symptoms. We hypothesize that genetic variants affecting ion homeostasis may increase susceptibility to concussion and/or contribute to dysfunctional recovery following TBI in some individuals. In this study we conducted whole exome sequencing (WES) of a cohort that had sustained one or more concussions and identified rare predicted deleterious genetic variants in known causative migraine genes, other neuronal ion channel or transporter genes, or genes affecting neurotransmission. We report rare and potentially damaging variants in such genes, suggesting that genetic vulnerabilities may contribute to concussion risk or its associated sequelae and warrants further investigation. 2. Materials and Methods Ethics The study was conducted in accordance with the Declaration of Helsinki, the protocol was approved by the Human Research Ethics Committee (HREC) of Queensland University of Technology (QUT), (Project approval number 1400000748), with informed consent was obtained from all participants. All experiments were performed according to their guidelines and regulation of QUT HREC. Cohort A cohort of 93 unrelated individuals who had suffered one or more concussions were recruited to the study. Index cases were collected through four avenues: n = 15 cases that had developed severe reactions to trivial head trauma and referred for FHM gene testing, but negative for pathogenic variants in known genes. Their clinical presentations and DNA collection have been described previously [39]. Sample identification (ID) numbers: R#. n = 11 participants were recruited through Brisbane hospitals with diagnosed concussion. Sample IDs: BBB#. n = 32 participants were recruited through local sporting groups and campus recruitment. Of these, 21 had concussion diagnosed by a medical professional and the remainder are self-reported. Twenty reported multiple concussions in the collected questionnaire data. Sample IDs: C#, CN#. n = 35 Australian Defence Force veterans who had previously sustained concussion/s were recruited through the Gallipoli Medical Research Foundation - Greenslopes Private Hospital (GMRF-GPH) Biobank. Sample IDs: P#. Response to concussion in the participants varied from no severe or long-lasting symptoms to persistent and ongoing symptoms including migraine, memory problems, fatigue, and vertigo from 3 months to >1 year post concussion event. Available information related to participant’s concussion history and symptoms is provided in Supplementary Table 1. For some cases family members were also recruited (n=15). DNA extraction and Whole Exome Sequencing Genomic DNA was isolated from either whole blood samples using QIAamp DNA Blood Mini Kits (Qiagen, Hilden, Germany), or from saliva using ORAgene-DNA OG-500 kits and PrepIT reagent (DNA Genotek, Stittsville, Canada) as per the manufacturer's instructions. We have previously shown that results for WES using DNA obtained from either blood or saliva is comparable [40]. Extracted blood DNA samples were available from the GMRF-GPH Biobank samples. Next-generation sequencing libraries for WES were constructed using Ion AmpliSeqTM Exome RDY Library Kits (Cat. no. 4489837 Rev A.0, Thermo Fisher, Scoresby, VIC, Australia) according to the manufacturer's protocol. The libraries were sequenced on the Ion S5 plus sequencer, using Ion v550 Chips (Thermo Fisher Scientific, Carlsbad, Ca., USA). Sequence reads were aligned to the human reference genome (hg19), the variants were called and the VCF files were generated using the Ion Torrent Suite software (Thermo Fisher Scientific, Carlsbad, Ca., USA). The VCF files were then uploaded to the locally hosted Ion Reporter Server software (v5.12) for automated variant annotation and filtering. The Binary Alignment/Map (BAM) bam format files were uploaded into the Integrative Genomics Viewer (IGV v2.3) software (http://www.broadinstitute.org/igv), to visually examine potential variants. Variant Curation Tiered analysis of WES data was performed to explore rare genetic variants in relevant genes. Exome variants were filtered for analysis to identify variants in genes i) causally implicated in severe types of migraine (CACNA1A, ATP1A2, and SCN1A) ; ii) ion channel and transporter genes ( n = 353 genes); and iii) genes affecting neurotransmission ( n = 220 genes) selected using the following gene ontologies: neural, neurological, brain, ion channel, and neuro* - Gene Ontology 20171101 (Tier 1-3, respectively). Gene lists for ion channel and neurotransmitter-related genes are in Supplementary Table 2. The three tiers of analysis were performed through Ion Reporter v5.12 filtering (Thermo Fisher). Identified variants were then filtered to include only variants that i) affected amino-acid composition of the protein; ii) had minor allele frequency (MAF) <0.02 in the gnomAD NFE cohort c2.1.1 (exomes); iii) were predicted to be damaging by two or more in silico analysis tools (SIFT version 5.2.2 [41]; PolyPhen version 2.2.2 release 405c [42]; MutationTaster2021 [43]; CADD score based upon Ensembl Ch37 [44]); iv) passed visual confirmation in IGV (v2.5.3); v) in genes with variants identified in multiple (two or more) unrelated patients. A post hoc manual selection was then undertaken based on literature and known biological relevance. Genotyping of selected variants in a migraine case-control cohort To assess frequencies of the channel-related variants detected in the concussion cohort in independent samples some genes/variants of interest in ATP7B , CACNB2 , SCN8A , SCN9A , and SCN10A were prioritised for genotyping in an Australian cohort of 280 migraine cases and 280 sex- and age-matched controls. Genotyping was performed via a multiplex MassARRAY assay (Agena Bioscience, San Diego, CA, USA). Primers were designed using Assay Design Suite v3.0 software for: ATP7B variants c.122A>G (p.Asn41Ser), c.1555G>A (p.Val519Met), c.2383C>T (p.Leu795Phe), c.2972C>T (p.Thr991Met), c.3700G>T (p.Val1234Phe), and c.3859G>A (p.Gly1287Ser); CACNB2 variants c.503G>A (p.Cys168Tyr) and c.1357C>T (p.Leu453Phe); SCN8A variant c.3076C>T (p.Arg1026Cys), SCN9A variants c.684C>G (p.Ile228Met), c.1109C>T (p.Thr370Met), c.3734A>G (p.Asn1256Ser) and c.3799C>G (p.Leu1278Val); and SCN10A variants c.2530C>T (p.Arg844Cys), c.3859G>A (p.Val1287Ile), and c.4585G>A (p.Ala1529Thr). Sequences available upon request. Not all variants of interest were genotyped due to assay designability or cost constraints. Primers were obtained from Integrated DNA Technologies (Singapore). Genotyping was conducted according to manufacturer’s protocols using PCR and iPLEX MassARRAY reagents on a matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry platform (Agena Biosciences, San Diego, CA, USA). Genotypes were called with Typer 4.0 software. Assays for SCN9A p.Ile228Met and SCN10A p.Val1287Ile variants failed and were not further analysed. Rare Variant Burden Analysis Rare variant burden analysis focused on the rare variants identified in the known FHM genes and other ion channel genes reported in this study. Counts of these variants were compared with the numbers observed in a general population control group obtained from the gnomAD database, selecting non-Finnish Europeans as most similar to the ancestral background of the recruitment population in Australia, using a Fisher's Exact test to determine statistical significance. Odds ratios were calculated as an estimate of effect size. 3. Results Single Variant analysis Annotated WES data from 93 unrelated individuals that have sustained one or more concussions was filtered to focus on rare (MAF <0.02), protein coding variants in known causative migraine genes, ion channel genes, or genes affecting neurotransmission (Supplementary Table 2) in accordance with our hypothesis that genetic vulnerabilities in these genes contribute to increased concussion risk. Rare amino acid changing variants that were predicted to be damaging according to at least two of the in silico prediction tools used were identified. 61.5% of these were predicted damaging by all four tools. In total, 62 rare missense variants were identified across 24 genes in 59 (63%) participants, with 26 participants harboring two or more candidate variants. All identified variants were heterozygous in participants. Tables 1, 2 and 3 detail the 62 variants identified in the three tiers of analysis: i) known migraine causative genes; ii) ion channel and transporter genes; and iii) genes affecting the neurotransmission, respectively, and include results of in silico predictions, summaries of current ClinVar classifications, and the gnomAD MAF for each in non-Finnish Europeans. Genes carrying identified variants included calcium channels ( CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1I, CACNB2 ), sodium channels ( SCN1A, SCN8A, SCN9A, SCN10A ), ATPases ( ATP10A, ATP13A4, ATP7B ), potassium channels ( KCNJ10, KCNT2 ) and various genes involved in neurotransmission ( CHAT, DAGLB, KIF17, NRG1, SNCAIP, SV2C, SYT9, UNC13B ). The genes carrying most variants across the cohort were: SNCAIP with four variants found across 10 participants including p.Glu709Gln in five participants and p.Arg806His in three participants; SCN9A with six variants identified across seven participants, including p.Asn1256Ser identified in three participants and one participant carrying two potentially damaging variants p.Leu1278Val and p.Ile228Met; ATP7B with six variants across six participants; CHAT with three variants identified in six participants including p.Arg561Gln in three participants; KIF17 with three variants across four participants, including p.Arg111Gly in two participants; SCN8A with the p.Arg1026Cys variant present in four participants; SYT9 with two variants across four participants, including p.Leu353Val identified in three participants; CACNA1A with one variant, p.Ala454Thr identified in three participants; and SCN10A with four variants across four participants. Some related individuals were available to look at segregation of variants in family members (Supplementary Tables 3 and 4), although, limited by small pedigrees and the fact that some kind of head trauma is required to be considered a case, we were unable to reach any strong conclusions. Fifteen variants identified in the concussion cohort were further genotyped in a migraine case-control cohort of 280 migraine cases and 280 age- and sex-matched controls via an Agena MassARRAY plex to confirm their frequency in a population collected from a similar geographical background, or with some symptomatic overlap (i.e. migraine). As results presented in Table 4 show, the channel variants identified in the concussion cohort were confirmed to be rare in general populations, and they do not appear to be particularly associated with migraine which is a common symptom of concussion. Although all the variants we identified were predicted to be deleterious, there is insufficient evidence to suggest that any are pathogenic in a monogenic autosomal dominant manner, as the participant’s symptoms of concussion were precipitated with head trauma. However, the results suggest that variants across ion channels and neurotransmitter genes that may be sub-clinical could plausibly confer increased susceptibility to concussion and exacerbate post injury ionic fluxes post-TBI under limited energy/recovery conditions. Rare variant burden analysis on ion channel genes Rare variant burden analysis focusing on the variants identified in the 16 ion channel genes from the Tier 1 and 2 analyses (Tables 1 and 2) was conducted to test whether there was enrichment (increased prevalence) of the damaging variants identified in the ion channel gene set in the concussion participants compared to a general population control group obtained from the gnomAD database (non-Finnish Europeans). As detailed in Supplementary Table 5, in our concussion cohort we identified 43 different rare, amino acid changing variants in 16 ion channel and ion channel transporter genes, according to our filtering criteria. The overall prevalence of damaging alleles was rare (<0.02) in both the case and control groups. In the concussion group, a total of 51 predicted damaging alleles at these loci were observed. This prevalence (0.64%) was ~5-fold greater than the prevalence of these alleles observed in the gnomAD population control group (0.12%) and significantly different by Fisher’s Exact test (Odds Ratio = 5.44, CI: 4.13, 7.18; P < 0.0001). Gene-based burden testing was not conducted due to the limited size of the concussion cohort. Table 1: Details of rare genetic variants identified in known migraine causative genes Gene Variant details Bioinformatic predictions GnomAD NFE data Locus Ref Amino Acid Change Coding change SNP ID CLINVAR Samples with Variant SIFT pred Polyphen2 HDIV pred Mutation Taster pred CADD phred Variant Allele count Total Allele count Freq CACNA1A 19:13428124 C p.Ala454Thr c.1360G>A rs41276886 likely benign (14) – Condition: Various neurological disorders CN7 P034 P038 T D D 24.1 265 47808 0.005543 SCN1A 2:166848003 G p.Arg1917Gly c.5749C>G rs121917956 likely benign (12) – Condition: Various neurological disorders CN11 C2 D D D 22.0 67 48282 0.001388 GnomAD NFE = allele frequency of non-Finnish Europeans, GnomAD allele count is based upon v2.1.1 (exomes). SIFT is based on version 5.2.2; PolyPhen is based on version 2.2.2 release 405c; MutationTaster2021; CADD score is based upon Ensembl Ch37. Table 2: Details of rare genetic variants identified in ion channel and ion transporter genes Gene Variant details Bioinformatic predictions GnomAD NFE data Locus Ref Amino Acid Change Coding change SNP ID CLINVAR Samples with Variant SIFT pred Polyphen2 HDIV pred Mutation Taster pred CADD phred Variant Allele count Total Allele count Freq ATP10A 15:25947181 G p.Ala881Val c.2642C>T rs142704035 . R170 a D D D 32 16 113700 0.000141 15:26108002 T p.Glu81Gly c.242A>G rs368768805 . CN27 D D D 24.7 11 107790 0.000102 ATP13A4 3:193132450 T p.Asn978His c.2932A>C rs770185624 . CN18 T B D 22.3 5 113740 0.000044 ATP7B 13:52511656 C p.Gly1287Ser c.3859G>A rs762866453 Conflicting classifications of pathogenicity (6) relating to Wilson Disease P254 D D D 27.6 1 113286 0.000009 13:52511815 C p.Val1234Phe c.3700G>T rs193922108 . P018 D D D 33 0 113194 0.000000 13:52520508 G p.Thr991Met c.2972C>T rs41292782 Conflicting classifications of pathogenicity (9) relating to Wilson Disease C4 D D D 33 266 112746 0.002359 13:52531716 G p.Leu795Phe c.2383C>T rs751710854 Pathogenic/Likely pathogenic (9) relating to Wilson Disease R211 b D D D 28.3 4 113288 0.000035 13:52542732 C p.Val519Met c.1555G>A rs192957846 Uncertain Significance (5) relating to Wilson disease CN25 D D D 29.3 127 113118 0.001123 13:52549234 T p.Asn41Ser c.122A>G rs201738967 Pathogenic/Likely pathogenic (12) relating to Wilson Disease P224 D D D 24.4 55 113168 0.000486 CACNA1B 9:140952560 G p.Arg1389His c.4166G>A rs184841813 Uncertain Significance (2) BBB19 D P D 34 78 113040 0.000690 9:141015296 C p.Ser2151Leu c.6452C>T rs200034261 Uncertain Significance (2) P235 D D D 29.9 37 75310 0.000491 CACNA1C 12:2690844 A p.Ile662Leu c.1984A>C . . R259 c D B D 23.1 . . . 12:2774859 A p.Tyr1552Cys c.4655A>G rs2153709630 Uncertain Significance (1) – Condition: Long QT Syndrome C5 D D D 32.0 . . . 12:2800220 A p.Asn2174Ser c.6521A>G rs201090446 Conflicting classifications of pathogenicity (9) BBB12 D D D 24.2 69 104020 0.000663 CACNA1D 3:53787624 A p.Asn1254Ser c.3761A>G rs147146258 . P186 T B D 22.9 78 113768 0.000686 3:53837487 C p.Arg1845Trp c.5533C>T rs144688228 Conflicting classifications of pathogenicity (3) – Condition: not Provided CN4 D B D 23.6 17 113770 0.000149 3:53844173 G p.Gly2034Ser c.6100G>A rs368340190 Uncertain Significance (1) – Condition: not Provided CN15 T B D 20.5 7 113558 0.000062 CACNA1E 1:181706777 C p.Ser1180Leu c.3539C>T rs202226007 . P200 D D D 34 4 112714 0.000035 1:181759588 C p.Arg1932Trp c.5794C>T rs776416674 . BBB12 D D D 26.8 6 112858 0.000053 1:181767528 G p.Arg2167Gln c.6500G>A rs370385055 Conflicting classifications of pathogenicity (2) – Condition: not Provided P242 D P D 34 7 112966 0.000062 CACNA1I 22:40045653 C p.Ser537Leu c.1610C>T rs372904212 . P191 T D D 22.5 6 44670 0.000134 22:40081856 G p.Asp2005Tyr c.6013G>T rs771105041 . P186 D D N 29.4 42 27346 0.001536 22:39994250 C p.Arg111Gly c.331C>G rs751729397 . R211 b D P D 34 1 103132 0.000010 CACNB2 10:18789787 G p.Cys168Tyr c.503G>A rs773215003 Uncertain Significance (4) – Condition: various cardiovascular conditions P200 D D D 26.8 2 113632 0.000018 10:18827118 G p.Asp438Asn c.1312G>A rs778466195 Uncertain Significance (2) – Condition: cardiovascular phenotype and Brugada syndrome 4 C2 D D D 34 1 113742 0.000009 10:18827163 C p.Leu453Phe c.1357C>T rs145638628 Conflicting classifications of pathogenicity (4) – Condition: cardiovascular phenotype and Brugada syndrome 4 CN29 D D D 29.0 48 113762 0.000422 KCNJ10 1:160011262 T p.Lys354Arg c.1061A>G rs142596580 Uncertain Significance (9) – Condition: Condition: various including EAST syndrome and non-syndromic hearing loss CN32 D D D 26.7 54 113678 0.000475 1:160012271 G p.Arg18Trp c.52C>T rs138457635 Uncertain Significance (7) – Condition: Condition: various including EAST syndrome and non-syndromic hearing loss R117 d D D D 27.7 78 113716 0.000686 KCNT2 1:196250115 T p.Lys929Glu c.2785A>G rs1659036452 . CN7 D P D 22.6 . . . 1:196309627 T p.Ile543Leu c.1627A>C rs780602272 . P095 T B D 23.8 5 113102 0.000044 SCN9A 2:167089942 G p.Leu1278Val (p.Leu1267Val)* c.3832C>G rs180922748 Conflicting classifications of pathogenicity (16) – Condition: Various including pain and seizure disorders CN10 D D D 26.5 212 102260 0.002073 2:167094638 T p.Asn1256Ser (p.Asn1245Ser)* c.3767A>G rs141268327 Conflicting classifications of pathogenicity (24) – Condition: Various including pain and seizure disorders R211 b P026 R171 e D D D 23.9 837 111518 0.007506 2:167108386 G p.Arg1121Trp (p.Arg1110Trp)* c.3361C>T rs190664764 Conflicting classifications of pathogenicity (6) – Condition: pain and seizure disorders R256 D . N 24.0 166 112256 0.001479 2:167137020 C p.Trp730Cys (p.Trp719Cys)* c.2190G>C rs202055175 Conflicting classifications of pathogenicity (15) – Condition: pain and seizure disorders BBB7 D D D 34 3 91662 0.000033 2:167145152 G p.Thr370Met c.1109C>T rs200391162 Conflicting classifications of pathogenicity (5) – Condition: pain and seizure disorders BBB27 D D D 32 1 102700 0.000010 2:167160752 G p.Ile228Met c.684C>G rs71428908 Conflicting classifications of pathogenicity (16) – Condition: pain and seizure disorders CN10 D D D 22.8 194 113030 0.001716 SCN10A 3:38743402 C p.Ala1529Thr c.4585G>A rs757916036 . P232 D D D 34 1 113512 0.000009 3:38753882 C p.Val1287Ile c.3859G>A rs145032037 . CN1 D D D 34 126 113524 0.001110 3:38755450 C p.Arg1268Gln c.3803G>A rs138832868 Conflicting classifications of pathogenicity (7) – Conditions: pain disorders and cardiovascular phenotypes BBB3 D B D 25.5 313 113532 0.002757 3:38770143 G p.Arg844Cys c.2530C>T rs140158387 Uncertain significance (2) - Conditions: Cardiovascular phenotypes P307 D D D 35 2 113548 0.000018 SCN8A f 12:52162823 C p.Arg1026Cys c.3076C>T rs117217073 Conflicting classifications of pathogenicity (6) – Condition: seizure disorders CN18 R167 BBB15 P194 D D D 24.5 1663 112888 0.014730 GnomAD NFE = allele frequency of non-Finnish Europeans, GnomAD allele count is based upon v2.1.1 (exomes). SIFT is based on version 5.2.2; PolyPhen is based on version 2.2.2 release 405c; MutationTaster2021; CADD score is based upon Ensembl Ch37. * Variant has previously been described in the literature with alternate protein residue number as annotated against a different transcript. a R170 A rare variant in ATP10A was previously reported in Ibrahim et al (2020) [39]. b R211 Rare variants in ATP7B and CACNA1I were previously reported in Ibrahim et al (2020). c R259 Rare variant in CACNA1C was previously reported in Ibrahim et al (2020). d R117 Rare variant in KCNJ10 was previously reported in Ibrahim et al (2020). e R171 also carries a rare variant in GRIK1 that is predicted to be deleterious as previously reported in Ibrahim et al (2020), not listed here as no other sample in this cohort carries a rare, potentially deleterious variant in this gene. f Some regions of the SCN8A gene have poor WES coverage with Ion AmpliSeqTM Exome Kits, so some variants in this gene may be missed. Table 3: Details of genetic variants identified in neurotransmission-related genes Gene Variant details Bioinformatic predictions GnomAD NFE data Locus Ref Amino Acid Change Coding change SNP ID CLINVAR Samples with Variant SIFT pred Polyphen2 HDIV pred Mutation Taster pred CADD phred Variant Allele count Total Allele count Freq CHAT 10:50835688 G p.Arg323His c.968G>A rs200176236 Likely Benign (1) – Condition: familial infantile mysathenia CN41 D D D 31 29 113718 0.000255 10:50856643 C p.Leu458Phe c.1372C>T rs76014951 Benign/Likely Benign (6) – Condition: familial infantile mysathenia CN32 P191 T D D 26.9 569 112684 0.005050 10:50863188 G p.Arg561Gln c.1682G>A rs80097077 Benign/Likely Benign (7) – Condition: familial infantile mysathenia CN11 BBB3 R118 a D D D 27.2 1188 113628 0.010460 DAGLB 7:6449794 A p.Ile596Thr c.1787T>C rs139753251 Benign (1) – Condition: Not provided CN26 P242 D D D 25.4 896 94702 0.009461 KIF17 1:21009189 T p.Glu807Ala c.2420A>C rs115257742 . CN32 D D D 28.6 188 113682 0.001654 1:21042033 T p.Arg111Gly c.331A>G rs35835983 . CN6 BBB17 D P D 23 1966 113480 0.017320 1:21044007 C p.Glu65Lys c.193G>A rs147438943 . CN27 T P D 24.9 709 110288 0.006429 NRG1 8:32617888 C p.Thr416Ser c.1247C>G rs62497784 Likely Benign (1) – Condition: Not provided BBB17 T D D 22.3 405 113256 0.003576 SNCAIP 5:121759069 G p.Val213Met c.637G>A rs201152226 . P095 D P D 17.65 8 113352 0.000071 5:121786403 C p.Arg621Cys c.1861C>T rs28937592 Likely Benign (4) – Condition: Parkinson disease P160 D D D 27.5 620 113618 0.005457 5:121786667 G p.Glu709Gln c.2125G>C rs55712196 Likely Benign (3) – Condition: Parkinson disease CN28 C4 R222 P194 P178 D D D 24.6 1418 113392 0.012510 5:121786959 G p.Arg806His c.2417G>A rs140850272 Benign (2) – Condition: Parkinson disease R259 P027 P202 D D D 28.5 1552 113672 0.013650 SV2C 5:75581035 T p.Val321Glu c.962T>A rs762537711 . P186 D P D 29.2 3 113238 0.000026 5:75591631 G p.Asp456Asn c.1366G>A rs756018103 . C7 T P D 25.7 3 112560 0.000027 SYT9 11:7324378 G p.Arg85Gln c.254G>A rs773842068 . R211 D P D 24.1 1 113724 0.000009 11:7437285 C p.Leu353Val c.1057C>G rs117876446 . CN1 P202 P200 D D D 25 1111 113672 0.009774 UNC13B 9:35380598 G p.Arg697Gln c.2090G>A rs144007866 . P194 T D D 31 29 113746 0.000255 9:35381587 G p.Ser760Ile c.2279G>T rs911067546 . R150 b D P D 20.9 . . . 9:35396516 C p.Asn1035Lys c.3105C>A rs918241456 . CN29 T D D 22.2 1 113586 0.000009 GnomAD NFE = allele frequency of non-Finnish Europeans, GnomAD allele count is based upon v2.1.1 (exomes) SIFT is based on version 5.2.2; PolyPhen is based on version 2.2.2 release 405c; MutationTaster2021; CADD score is based upon Ensembl Ch37 a R118 also carries a rare variant in KCNAB1 that is predicted to be deleterious as previously reported in Ibrahim et al (2020) [39], although not listed here as no other sample in this cohort carries a rare, potentially deleterious variant in this gene. b R150 also carries a rare variant in GABRG1 that is predicted to be deleterious as previously reported in Ibrahim et al (2020), not listed here as no other sample in this cohort carries a rare, potentially deleterious variant in this gene. Table 4: Genotypic analysis of ion channel variants identified in concussion study in general migraine case-control cohort Gene Variant gnomAD MAF (NFE) No. variant alleles in migraine cases (n=280) / Frequency* No. variant alleles in controls (n=280) / Frequency* ATP7B p.Asn41Ser 0.000486 0 0 p.Val519Met 0.001123 1 / 0.00179 0 p.Leu795Phe 0.000035 0 0 p.Thr991Met 0.002359 2 / 0.00357 3 / 0.00536 p.Val1234Phe 0 0 0 p.Gly1287Ser 0.000009 0 0 CACNB2 p.Cys168Tyr 0.000018 0 0 p.Leu453Phe 0.000422 1 / 0.00179 1 / 0.00179 SCN8A p.Arg1026Cys 0.014730 2 / 0.00357 7 / 0.0125 SCN9A p.Thr370Met 0.000010 0 0 p.Asn1256Ser 0.007506 1 / 0.00179 0 p.Leu1278Val 0.002073 1 / 0.00179 0 SCN10A p.Arg844Cys 0.000018 0 0 p.Val1287Ile 0.001110 0 0 p.Ala1529Thr 0.000009 0 0 * If number (no.) of variant alleles is >0. 4. Discussion Exploring the hypothesis that rare genetic variation across known causative migraine genes, ion channels and neurotransmission-related genes may contribute to an increased vulnerability to concussion, we found that 63% of participants who had sustained concussion carried at least one rare, potentially deleterious (based on in silico prediction) missense heterozygous variant in an ion channel or neurotransmitter-related gene. Furthermore, many of the prioritised genes bore variants in multiple unrelated cases, with eight genes carrying variants identified in four or more participants. Combined, the data identifies genes with plausible involvement in concussion susceptibility and suggests the need for further investigation of the functional effects of the observed variants. Familial hemiplegic migraine genes Causal genes for FHM – CACNA1A (FHM1), ATP1A2 (FHM2), or SCN1A (FHM3) – were specifically included in the analysis due to the symptomatic overlap of these disorders with the neurologic symptoms that often present after concussion and the dysregulation of ion fluxes and neurotransmission that occurs in both migraine and concussion patients. We had previously found that a high proportion (35%) of hemiplegic migraine cases with pathogenic ATP1A2 missense variants were noted to have incidence of concussion or concussion-related symptoms after mild head trauma [45]. These individuals had been excluded from the current study and no further rare ATP1A2 variants were identified in this cohort. FHM patients with CACNA1A mutations may also be highly sensitive to head impacts [34,35]. Three unrelated participants had a rare missense variant (p.Ala454Thr) in CACNA1A , which encodes the pore-forming subunit of the voltage-gated calcium channel Ca V 2.1 [46] and plays an important function in controlling neurotransmitter release at presynaptic terminals [47-49]. p.Ala454Thr is likely benign in ClinVar, although was previously found in a heterogeneous ataxic disorder [50] and shown to confer loss-of-function (LoF) effects, altering the voltage dependence of steady-state inactivation and interactions between Cav2.1 and SNARE proteins leading to a decreased channel coupling to exocytosis [51]. Such functional effects could potentially contribute to dysregulation of the ion fluxes that occur in concussion. A p.Arg1917Gly variant in SCN1A , which encodes the voltage-gated sodium channel Na V 1.1, was identified in two unrelated participants. Notably both participants also have a second rare missense variant in other genes of interest, i.e. CHAT (C2) or CACNB2 (CN11). Although SCN1A p.Arg1917Gly is classified as likely benign in ClinVar, participant CN11 reported multiple concussions with ongoing photo- and phono-sensitivity and migraine with aura (age of onset 30 years). We therefore suggest that while this heterozygous variant may not lead to the severe FHM phenotype under normal conditions, head trauma may act as a precipitant of disturbance leading to the migraine with aura phenotype post-concussion, with or without additional variant burden in other ion channel or neurotransmission related genes. Ion channel genes and ion transporter genes An expanded analysis of a panel of 353 ion channel and related genes identified potential causal variants in other ion channel genes in concussion cases. Rare variants were detected in genes encoding calcium channel a1 ( CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1I ) and auxiliary subunits ( CACNB2 ), sodium channel a1 subunits ( SCN1A, SCN8A, SCN9A, SCN10A ), ATPases ( ATP7B , ATP10A, ATP13A4 ), and potassium channel subunits ( KCNJ10, KCNT2 ). The highest number of damaging rare variants in ion channel-related genes was detected in SCN9A (i.e. six different variants in eight cases). Calcium channel genes Cellular calcium influx is a key component of the neurometabolic cascade following a deceleration injury as highlighted by Giza and Hovda [24]. “ CACNA1x ” are a family of conserved genes that code the 10 different pore‐forming α1 subunits of voltage‐gated calcium channels (VGCCs). Including CACNA1A discussed previously, 18 rare variants were identified across seven VGCCs, with three participants carrying two missense variants in two different calcium channel genes (BBB12— CACNA1C p.Asn2174Ser and CACNA1E p.Arg1932Trp; P186— CACNA1I p.Asp2005Tyr and CACNA1D p.Asn1254Ser; and P200— CACNA1E p.Ser1180Leu and CACNB2 p.Cys169Tyr). Three rare variants were identified in CACNA1I . The p.Arg111Gly variant in R211, who had severe migraine and ataxia following head injury and a family history of migraine, had been previously reported [39]. Functional testing of p.Arg111Gly variant Ca V 3.3 channels by patch-clamp assay found that it reduced current density in comparison with wild-type [52]. The other two CACNA1I variants identified in unrelated cases should be considered for similar functional follow-up. The CACNA1B p.Arg1389His variant found in BBB19 has previously been linked to dystonia, albeit with conflicting results [53,54]. Functional analysis of this variant in a study of a family with myoclonus-dystonia syndrome with cardiac arrhythmias showed that mutant channels carried less current when open compared with wild-type Ca V 2.2 channels, consistent with a gain-of-function (GoF) [53]. Three variants each were found in nine different participants in the CACNA1C, CACNA1D, and CACNA1E genes, which encode the a1 subunits of Ca V 1.2, Ca V 1.3, and Ca V 2.3 channels, respectively, which have important roles in a variety of neuronal processes [55]. CACNA1C has been associated with a spectrum of cardiac and neurological disorders including Timothy Syndrome [56]. The CACNA1C p.Asn2174Ser variant (also annotated as p.Asn2091Ser in some transcripts) has been previously identified in a case of sudden unexplained death in the young (SUDY) and shown to exhibit minor kinetic alterations in functional tests [57]. CACNA1D , expressed in post-synaptic neurons, is associated with increased risk of neuropsychiatric disease and epilepsy [58], while CACNA1E Ca V 2.3 channels initiate rapid synaptic transmission through high-voltage-activated, rapidly inactivating R-type calcium currents in the central nervous system (CNS), with de novo missense CACNA1E variants causal for developmental and epileptic encephalopathies [59]. Sodium channel genes Sodium channels are also involved in a variety of neurological disorders including migraine, epilepsy, and pain disorders. Furthermore, increasing evidence suggests that concussion can induce forms of sodium channelopathy [60,29]. The detection of multiple variants in this class of genes in individuals that had sustained concussion may indicate that vulnerability to, or more severe reactions to concussion, could arise from functional variants which effect regulation of sodium ion fluxes. SCN9A encodes the voltage-gated sodium channel subunit Na V 1.7 which plays a significant role in nociception signaling and pain mechanisms. Pathogenic GoF variants in SCN9A that affect neuronal excitability have been associated with varying clinical presentations, including primary erythromelalgia, paroxysmal extreme pain disorders, and peripheral neuropathy [61-63]. SCN9A variants have also been associated with various epilepsy and seizure disorders [64,65]. Six rare missense mutations at residues highly conserved across mammalian orthologues were identified in the SCN9A gene across the concussion cohort, four of which have been previously associated with known pain-related disorders [63,66]. SCN9A p.Ile228Met has been functionally shown to impair slow-inactivation (i.e. GoF) and can increase the excitability of trigeminal and dorsal root ganglion neurons [66,67]. Estacion and colleagues identified the variant in the three patients showing phenotypic diversity of pain disorders—one primary erythromelalgia, and two with small fibre neuropathy [66]. Participant CN10 with the p.Ile228Met variant reported a single concussion with ~18 months recovery time, however, suffered ongoing mental fatigue, visual disturbances, and occasional memory disturbances. Interestingly, they also have a SCN9A p.Leu1278Val variant. SCN9A variants including p.Leu1278Val have been found in Dravet syndrome patients alongside SCN1A mutations; Singh et al. hypothesised that carriers of SCN9A variants might be asymptomatic or present with infrequent febrile seizures due to incomplete penetrance and variable expressivity, but have a modifier effect when combined with SCN1A variants in Dravet syndrome, contributing to the variable presentation [64]. The SCN9A p.Asn1256Ser variant was found in three different participants reporting confusional migraine or migraine-like episodes following head injury. The SCN8A p.Arg1026Cys variant was present in four unrelated participants, an allele frequency of 2.2% in this cohort, while at ~1.4% in general population databases. SCN8A encodes the voltage-gated sodium channel subunit Na V 1.6, and pathogenic variants can be classed as either LoF or GoF with variable consequences. Pathogenic GoF variants generally present with early-infantile epilepsies, while LoF variants generally lead to later-onset epilepsies, absence epilepsy, neurodevelopmental delays, and behavioral features such as attentional dysfunction [68,69]. Interestingly, a swine model that had undergone experimental concussion showed widespread loss of Na V 1.6 channel isoforms in white matter axons at 6 h and 72 h after injury, which recovered by two weeks post-injury, and may underlie the brain network dysfunction that occurs after concussion [29]. A loss of Na V 1.6 and changes in nodes of Ranvier structures were similarly observed in the white matter of post-mortem human brain samples with TBI [29]. Four different rare SCN10A missense variants in four concussion participants were identified. SCN10A encodes a neuronal voltage-gated sodium channel subunit of Na V 1.8, an important regulator of neuronal excitability. SCN10A pathogenic variants are most commonly associated with cardiac disorders [70], but also have been associated with cases of autism spectrum disorder [71,72], pain perception and seizures [73], and small fibre neuropathy [63]. Some of the sodium channels variants we detected have previously been shown to have clinical relevance and/or functional effects. We hypothesize that the variants may contribute to minor effects on sodium channel function, which, in the event of trauma, are sufficient to interfere with normal neuronal function and homeostasis. The finding of multiple rare and potentially damaging variants in sodium channel genes in our concussion cohort aligns with the proposal that sodium channelopathy underlies concussion symptoms [29,60]. Our results could be particularly relevant in cases of multiple concussions to the finding that traumatic axonal injury from concussion induces a form of sodium channelopathy on axons that greatly exaggerates the pathophysiologic response to subsequent mild injuries [60]. ATPase genes Three ATPase related genes with multiple rare variants were identified in the study: ATP10A ( n = 2 variants), ATP13A4 ( n = 1 variant, also present in an affected family member, Supplementary Table 4), and ATP7B ( n = 6 variants). The ATP10A p.Ala881Val variant in participant R170 who presented with confusional migraine following minor head injury had been previously reported [39], and now a second rare, likely damaging ATP10A variant (p.Glu81Gly) in a case presenting with migraine without aura and memory problems after several concussions was identified. Pathogenic LoF variants in ATP7B cause the autosomal recessive Wilson disease due to impaired copper metabolism in which the basal ganglia and liver undergo changes that express themselves in neurologic manifestations, and signs of cirrhosis, respectively [74]. Neurological manifestations include changes in personality and behaviour, similar to what may occur following TBI. We previously reported the heterozygous ATP7B p.Leu795Phe variant in patient R211 that presented with severe migraine and ataxia following head injury [39]. Included with the current study, we have identified six participants out of 93 who have had concussion with a heterozygous novel or rare ATP7B missense variants previously described as pathogenic, or of uncertain significance, for Wilson disease, while the frequency of heterozygous pathogenic ATP7B variants carriers in the population is estimated as only ~1 per 90 [75]. It is possible that heterozygous mutations in this gene may contribute to concussion with head injury acting as trigger on the risk allele [39], reflecting the role of metal ions in neurophysiology, and the dysregulation that may occur in TBI [76]. Potassium channel genes Potassium channels are a diverse ion channel group with five types defined by their activators: voltage-gated, calcium-activated, inwardly rectifying, ATP-sensitive and sodium-activated [77]. Rare and likely deleterious variants were identified in potassium channel genes KCNJ10 and KNCT2 . KCNJ10 , a member of the inward rectifier-type potassium channel family (Kir4.1), has a role in maintaining the ionic environment in the extracellular space, acting as a modulator of neuronal activity and the glutamatergic system. Kir4.1 dysfunction has been linked to neurological conditions including depression and epilepsy [78], and it is downregulated in murine models of neurodegeneration, with resulting increased neuronal hyperexcitability a possible driver of neuronal loss [79]. We previously reported R117 carrying the p.Arg18Trp variant [39], who presented with recurrent episodes of pallor and vomiting following minor head injury, and sensitivity to loud noises and light for three weeks, while CN32 with a KCNJ10 p.Lys354Arg variant, had sustained multiple concussions, but reported no ongoing or long-term symptoms. KCNT2 encodes a sodium-activated potassium channel (also known as SLICK) which is widely expressed across the CNS, modulating membrane hyperpolarization and adapting neuronal firing patterns [80]. Pathogenic KCNT2 variants have been identified in development and epileptic encephalopathies (DEE) [81,80], although no functional or clinical data is available for the p.Lys929Glu and p.Ile542Leu variants identified here. Interestingly, another exploratory exome-based study of 50 concussion patients found multiple rare variants with predicted high impact in KCNN3 , which encodes a calcium-activated potassium channel (K Ca 2.3) that regulates neuronal excitability by dampening calcium mediated neuronal firing frequency [82]. It is possible that the functional effects of the channel variants identified in these studies are not significantly different from those of wild type channels, except perhaps in the context of significant ionic dysregulation as occurs in concussion. Further functional assays would be required to test this hypothesis. Neurotransmission-related genes As research has shown that following concussion there is a release of neurotransmitters such as glutamate [23], and that damaged neurons demonstrate reduced or inhibited neuronal signaling in some neuron subtypes [83], we hypothesized that genes in pathways regulating neurotransmission may also harbor genetic variants that play a role in concussion. Rare variants were identified in various neurotransmission-related genes including: CHAT (p.Arg323His, p.Leu458Phe, p.Arg561Gln), DAGLB (p.Ile596Thr), KIF17 (p.Glu807Ala, p.Arg111Gly, p.Glu65Lys), NRG1 (p.Thr416Ser), SNCAIP (p.Val213Met, p.Arg621Cys, p.Glu709Gln, p.Arg608His), SV2C (p.Val321Glu, p.Asp456Asn), SYT9 (p.Arg85Gln, p.Leu353Val) and UNC13B (p.Arg687Gln, p.Ser760Ile, p.Asn1035Lys). Further information on these genes is detailed in Supplementary Information 6. Several of these genes have been linked to cognitive function and particularly have been associated with Alzheimer’s and/or Parkinson’s disease. For example, ten participants in the concussion cohort had variants in the SNCAIP gene (five with p.Glu709Gln and three with p.Arg806His). SNCAIP encodes synuclein alpha-interacting protein or synphilin-1. It is enriched at synaptic terminals, has a role in regulating energy homeostasis and cellular ATP levels, and is associated with alpha-synuclein and inclusion bodies in Parkinson’s disease [84,85]. The relationship between Parkinson’s disease and head injury is not clearly understood, although some studies have shown increased risk of Parkinson’s disease in those who have suffered mild to moderate head injury. For example, a significant increased risk for Parkinson's disease diagnosis later in life was found in a cohort of 47,483 individuals with a concussion (Odds ratio = 1.57; 95% CI [1.41,1.75]; p <0.001) [86]. A similarly large study of veterans also identified 56% increased risk of Parkinson’s disease in military veterans who had suffered mild traumatic brain injury [87]. These data add to the body of evidence suggesting that there may be some overlap of the genetic risk factors for concussion and Parkinson’s disease. 5. Limitations We acknowledge the relatively small size of the cohort (n=93), which means we have limited analysis to an overall neuronal vulnerability hypothesis rather than grouping concussion outcomes and post-concussion symptoms, so some of our findings may be related to specific outcomes rather than initial vulnerability to concussion. We also suggest that generalizable conclusions will need to be explored in larger TBI/concussion cohorts, with clear groups based on concussion outcomes optimal for analysis. The limited sample size also meant we could not use a genome-wide approach for analysis or burden testing and acknowledge that targeting gene sets may miss important gene variants or identify rare variants that are not necessarily linked to our hypothesis. We have attempted to limit the latter through filtering to include only genes with predicted deleterious variants in more than one participant and propose that these genes are prioritized for further investigation to validate these findings. Not all individuals in the cohort had coding variants in the genes that were targeted for analysis, and our study does not preclude the roll of other genes, non-coding or common variants, and non-genetic mechanisms in concussion. 6. Conclusion In conclusion, we have identified potentially deleterious coding variants in a series of neuronal ion channels and other synaptic genes in study participants who had sustained concussion/s. Many of these genes have been previously linked to disorders that show overlapping symptomology with post-concussion symptoms. We propose that while many of the identified heterozygote variants may be subclinical under normal conditions, dysfunction may be revealed after head trauma which disrupts ion homeostasis and requires recovery of ionic and excitatory/inhibitory balance leading to the shared phenotypes post-concussion. Genes encoding ion channel proteins, especially those involved in calcium and sodium ion transport, are of particular interest. We also found many candidate variants in genes involved in neurotransmission, and that have been associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. The most recent consensus statement of concussion in sport notes that while currently genetic testing may be a valuable research tool in the study of concussion, it is not yet suitable for routine use in clinical practice [3]. Accordingly, our results provide important genetic information for further investigation to aid in developing useful markers for understanding concussion risk, predicting outcomes and prognosis, and in identifying potential targets for treatment strategies. Declarations Acknowledgements We thank all the participants who took part in this research and the Gallipoli Medical Research Foundation. We acknowledge investigators involved in the Gallipoli Medical Research Foundation project conception, recruitment and sample acquisition: PTSD Initiative Members of the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia - Sarah McLeay, Wendy Harvey, Madeline Romaniuk, Darrell Crawford, David Colquhoun, Ross McD Young, Miriam Dwyer, John Gibson, Robyn O'Sullivan, Graham Cooksley, Christopher Strakosch, Rachel Thomson, Joanne Voisey, and Bruce Lawford. Author contributions L.R.G., A.G., R.A.L., A.M.J.M.M., and D.R.N. conceptualized the study and acquired funding. Participant recruitment and sample collection was facilitated by L.R.G., R.A.S., O.D., and F.A.N.. N.M. and O.D. conducted the exome sequencing. H.G.S conducted additional variant confirmation and genotyping. Data analyses were carried out by N.M., H.G.S., B.H.M., O.D., and R.A.L.. B.H.M. wrote the first draft of the manuscript. H.G.S. and N.M. contributed to further writing, and all co-authors reviewed and provided advice on the manuscript. Funding This project was funded by a U.S. DOD Defense Health Program Congressionally Directed Medical Research Programs Traumatic Brain Injury and Psychological Health Research Program Investigator-Initiated Research Award FY18 (W81XWH-19-1-0098; PR180286) and an Australian National Health and Medical Research Council grant (NHMRC-APP1122387). Infrastructure used in the project was purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia - Queensland Node project. O.D. was a recipient of a QUT Faculty of Health Postgraduate Scholarship. Data availability Data supporting the findings of this study are available within the paper and supplementary tables. Full participant sequencing data is not openly available due to ethics stipulations and reasons of privacy, however, specific information about genetic variants or genes in participants are available upon reasonable request to the corresponding author. Data are located in controlled access data storage at Queensland University of Technology. The novel sequence variant identified in this paper has been submitted to dbSNP for inclusion in the next available build (submission ID number 2137544578). When the build is completed by dbSNP, data will be available at: https://www.ncbi.nlm.nih.gov/SNP/snp_viewTable.cgi?handle=GENOMICSRESEARCHCENT Conflicts of interest L.R.G. reports recent consultancy support from Teva, participates on the Aust Novartis migraine Advisory Board, and has received research support from VariantBio. She also serves as Chair for the Board of Censors, Diagnostic Genomics, Human Genetics Society Australasia. The other authors declare no conflicts of interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Ethics approval This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. 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Fam Med Community Health 8(3). https://doi:10.1136/fmch-2020-000390 Gardner RC, Byers AL, Barnes DE, Li Y, Boscardin J, Yaffe K (2018) Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study. Neurology 90(20):e1771–e1779. https://doi:10.1212/WNL.0000000000005522 Additional Declarations The authors declare potential competing interests as follows: L.R.G. reports recent consultancy support from Teva, participates on the Aust Novartis migraine Advisory Board, and has received research support from VariantBio. She also serves as Chair for the Board of Censors, Diagnostic Genomics, Human Genetics Society Australasia. The other authors declare no conflicts of interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Supplementary Files SupplementaryTable1Participantinformation.xlsx Supplementary Table 1. Available concussion information for study cohort SupplementaryTable2Ionchannelandneurogenelists.xlsx Supplementary Table 2. Ion channel and neuro gene lists SupplementaryTables3and4Familyandvariantinfov2.docx Available family members of index cases and variant segregation information SupplementaryTable5Ionchannelsburdenanalysis.xlsx Supplementary Table 5. Variants and allele counts for burden testing of ion channel genes SupplementaryInformation6.docx Supplementary Information 6. Extended discussion of neurotransmission-related genes with variants identified in the concussion cohort Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Technology","correspondingAuthor":false,"prefix":"","firstName":"Neven","middleName":"","lastName":"Maksemous","suffix":""},{"id":629606296,"identity":"e2f3623b-f0ae-4fd4-bf88-c9374454c887","order_by":2,"name":"Heidi G Sutherland","email":"","orcid":"","institution":"Queensland University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Heidi","middleName":"G","lastName":"Sutherland","suffix":""},{"id":629606297,"identity":"db580d41-cda2-44f5-844b-37e5b6b7d881","order_by":3,"name":"Robert A Smith","email":"","orcid":"","institution":"Queensland University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"A","lastName":"Smith","suffix":""},{"id":629606298,"identity":"a0fbc5b0-87d4-4823-bd26-69fb8d83c1c5","order_by":4,"name":"Omar Dabash","email":"","orcid":"","institution":"Queensland University of 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Griffiths","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIie3OsUoDMRzH8V/4Q27513PMUfsOJweiHOir9OjQpToXKrVQsMs9QvExOgmmBOriAwhOt3Tq4KJcN3PtgSjk7OiQL4EkkA//AD7fP+xov6kwmEICw/raRGT9JsoN2fMLwAcSRLm2RNwfQtS1Fh+P54qDcFVsH9LsCbR8Y1xmEye56dLJWikmCpLWop/lkL2U0Wsgg5iUVuMrItkWC2MJn7UZ9CeppshoO69I+GnJXSMR7zVRrcluirTEuAlvYoM9sf9Z9ZPcyORiHj8nLhIGg9Oi1GPF4XIdlbdpZzabFq+b4ajjIjjuwvD3lXYLiF3vqzEaovxBfD6fz/erLxgJRXVPsFQ/AAAAAElFTkSuQmCC","orcid":"","institution":"Queensland University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Lyn","middleName":"R","lastName":"Griffiths","suffix":""}],"badges":[],"createdAt":"2026-04-26 00:55:36","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9528680/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9528680/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108183840,"identity":"4cb9c9b6-afe5-4321-bf91-6aedbeb5e9fa","added_by":"auto","created_at":"2026-04-30 09:02:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":884781,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9528680/v1/61bb9f9c-2fe4-4a62-b6fc-62a9ad911268.pdf"},{"id":108082533,"identity":"5cd140d0-d94f-451d-b3af-a5cd19988a6b","added_by":"auto","created_at":"2026-04-29 07:58:30","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16613,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1. Available concussion information for study cohort\u003c/p\u003e","description":"","filename":"SupplementaryTable1Participantinformation.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9528680/v1/1b9b0d44b075601124904605.xlsx"},{"id":108182673,"identity":"2c6b1cbb-0d48-42f3-a350-fb9856571ca1","added_by":"auto","created_at":"2026-04-30 08:59:29","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18817,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 2. Ion channel and neuro gene lists\u003c/p\u003e","description":"","filename":"SupplementaryTable2Ionchannelandneurogenelists.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9528680/v1/5d2dfdc3a54ce7457ce42782.xlsx"},{"id":108082534,"identity":"322ba581-c073-4e8b-996a-e9261600e442","added_by":"auto","created_at":"2026-04-29 07:58:30","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19899,"visible":true,"origin":"","legend":"\u003cp\u003eAvailable family members of index cases and variant segregation information\u003c/p\u003e","description":"","filename":"SupplementaryTables3and4Familyandvariantinfov2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9528680/v1/0dd067c79638af8068246fb1.docx"},{"id":108181434,"identity":"03d8a6b4-12d0-475f-af47-e0371770b5b5","added_by":"auto","created_at":"2026-04-30 08:58:38","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":19083,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 5. Variants and allele counts for burden testing of ion channel genes\u003c/p\u003e","description":"","filename":"SupplementaryTable5Ionchannelsburdenanalysis.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9528680/v1/3077dbd9d68fd8fc727b5e7f.xlsx"},{"id":108082537,"identity":"9cd11233-c8d1-4f3e-b124-ac6f7edabefe","added_by":"auto","created_at":"2026-04-29 07:58:30","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":43832,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Information 6. Extended discussion of neurotransmission-related genes with variants identified in the concussion cohort\u003c/p\u003e","description":"","filename":"SupplementaryInformation6.docx","url":"https://assets-eu.researchsquare.com/files/rs-9528680/v1/bc4326faffceef852d3a97eb.docx"}],"financialInterests":"The authors declare potential competing interests as follows: L.R.G. reports recent consultancy support from Teva, participates on the Aust Novartis migraine Advisory Board, and has received research support from VariantBio. She also serves as Chair for the Board of Censors, Diagnostic Genomics, Human Genetics Society Australasia. The other authors declare no conflicts of interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.","formattedTitle":"\u003cp\u003eInvestigating vulnerability to concussion through rare ion channel and neurotransmitter genetic variants\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eConcussion is a condition of neurologic dysfunction resulting from biomechanical forces acting on the brain. Some individuals may be more susceptible to sustaining a concussion or display a range of neurological symptoms of varying severity. While most symptoms are transient and resolve in approximately two weeks, a subset of individuals develop post-concussion syndrome (PCS), experiencing symptoms such as headaches, dizziness, fatigue, and cognitive issues, that persist for months or even years [1-3]. Post-traumatic headache, often meeting the phenotypic criteria for migraine, is one of the most common symptoms following injury [4-6]. Why some people experience concussion with long-term neurological symptoms, and others do not, remains poorly understood. Inter-individual variability may be partly explained by injury severity, age, sex, or pre-injury health; however, there is growing evidence that genetic variation also influences both the likelihood of sustaining a concussion and the trajectory of recovery [7-9].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrevious small-scale genetic studies have investigated the association of concussion risk with genetic variants in genes with known neurological functions, including: Alzheimer\u0026rsquo;s disease risk \u003cem\u003eAPOE\u003c/em\u003e \u003cem\u003eE4\u003c/em\u003e allele [10-12] and \u003cem\u003eMAPT\u0026nbsp;\u003c/em\u003e[13,14]; \u003cem\u003eBDNF\u0026nbsp;\u003c/em\u003e[15,16]; glutamate transporters and receptors \u003cem\u003eSLC17A7\u0026nbsp;\u003c/em\u003e[17] and \u003cem\u003eGRIN2A\u0026nbsp;\u003c/em\u003e[18]; and the dopamine receptor gene \u003cem\u003eDRD4\u0026nbsp;\u003c/em\u003e[19]. Genome-wide association studies (GWAS) take a more agnostic approach, ideally with statistically robust sample sizes. In 2021 Kim et al. reported two gene loci with functions in neural development and axon outgrowth (\u003cem\u003eSPATA5\u003c/em\u003e and \u003cem\u003ePLXNA4\u003c/em\u003e) significantly associated with concussion risk [20]. A GWAS by Kals et al. that used the extended Glasgow Outcome Scale at 6 months post-TBI as a measure of TBI outcome found 13 genetic loci associated at a suggested level of significance, with several biologically plausible associations such as \u003cem\u003eDOC2A\u003c/em\u003e, which is involved in calcium-dependent neurotransmitter release, identified through supplementary transcription-wide association analysis [21]. A large GWAS of TBI in U.S. military veterans in 2024 identified 15 genome-wide significant loci mapping to 14 genes, including \u003cem\u003eAPOE\u003c/em\u003e, \u003cem\u003eNCAM1\u003c/em\u003e, \u003cem\u003eFOXP2\u003c/em\u003e, and \u003cem\u003eFTO\u003c/em\u003e, and found that TBI showed high genetic correlation with psychiatric and risk-taking traits [22]. These studies, with a focus on common genetic variants, support the genetic underpinnings of various aspects of concussion, including the likelihood of sustaining TBI or concussion, recovery profile, and co-occurring symptoms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudies investigating the mechanisms of TBI indicate that substantial ion fluxes and alterations to neurotransmission occur following injury [23-25]. This is characterised by an efflux of potassium (K\u003csup\u003e+\u003c/sup\u003e), alongside the release of excitatory neurotransmitters such as glutamate, and an influx of sodium (Na\u003csup\u003e+\u003c/sup\u003e) and calcium (Ca\u003csup\u003e2+\u003c/sup\u003e) into neurons, which likely result from altered membrane permeability following cellular distortion. These changes promote local and downstream neuronal depolarization through the activation of voltage-gated ion channels of subsequent neurotransmission. Following these acute events, ATP-dependent ion pumps are activated to restore ionic homeostasis. This process substantially increases neuronal energy demand and oxidative stress [23]. The resulting metabolic strain can lead to hyperglycolysis, which is further exacerbated by Ca\u003csup\u003e2+\u003c/sup\u003e-mediated disruption of mitochondrial function. Neuronal energy depletion can last for approximately 2 weeks [26], aligning with the typical recovery period for concussion\u0026nbsp;and highlighting the importance of these early molecular events in its pathophysiology. Changes in the subunit composition of ligand-gated ion channels following a TBI have also been reported in animal models\u0026nbsp;[27-29], and may correlate with the altered cognition and learning displayed by concussion sufferers\u0026nbsp;[30,31]. Thus, neurotransmitters and ion channels are involved in the earliest stages of cellular response to TBI\u0026nbsp;[32], and may represent key players in concurring severity after TBI at the cellular and metabolic level and development of persistent symptoms including post-traumatic headache and migraine.\u003c/p\u003e\n\u003cp\u003eFurther evidence of the potential role of genetic variation in concussion and its aftermath arises from the pathophysiological and symptomatic overlap of PCS with other neurological disorders, particularly the ion channelopathies. Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder in which migraine attacks are accompanied by motor dysfunction caused by rare pathogenic variants in ion channel, transporter, and synaptic genes [33]. Some individuals with FHM may have severe responses to trivial head trauma. For example, patients with FHM Type 1 (FHM1) caused by pathogenic variants in the calcium channel gene \u003cem\u003eCACNA1A\u003c/em\u003e may exhibit high sensitivity to head impacts; in cases involving the severe p.Ser218Leu mutation, even minor head injury can result in concussion, seizures, cerebral oedema, coma, or death\u0026nbsp;[34,35]. This phenotype closely resembles second-impact syndrome, where a subsequent mild injury following an initial concussion can lead to catastrophic cerebral oedema. FHM1 \u003cem\u003eCACNA1A\u003c/em\u003e mutations lead to a gain of Ca\u003csub\u003eV\u003c/sub\u003e2.1 channel function with increased Ca\u003csup\u003e2+\u003c/sup\u003e neuronal influx\u0026nbsp;[36].\u0026nbsp;Knock-in mouse models carrying human \u003cem\u003eCACNA1A\u003c/em\u003e mutations display enhanced glutamatergic neurotransmission and an imbalance between excitatory and inhibitory signalling, which facilitates cortical spreading depression (CSD)\u0026nbsp;and worsens outcomes after experimental TBI\u0026nbsp;[37,38]. Importantly, the dysregulated ion fluxes and neurotransmission that occur in FHM mirror the metabolic cascade observed post-TBI and may underlie acute post-concussive symptoms.\u003c/p\u003e\n\u003cp\u003eWe hypothesize that genetic variants affecting ion homeostasis may increase susceptibility to concussion and/or contribute to dysfunctional recovery following TBI in some individuals. In this study we conducted whole exome sequencing (WES) of a cohort that had sustained one or more concussions and identified rare predicted deleterious genetic variants in known causative migraine genes, other neuronal ion channel or transporter genes, or genes affecting neurotransmission. We report rare and potentially damaging variants in such genes, suggesting that genetic vulnerabilities may contribute to concussion risk or its associated sequelae and warrants further investigation.\u003c/p\u003e"},{"header":"2.\tMaterials and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki, the protocol was approved by the Human Research Ethics Committee (HREC) of Queensland University of Technology (QUT), (Project approval number 1400000748), with informed consent was obtained from all participants. All experiments were performed according to their guidelines and regulation of QUT HREC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCohort\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA cohort of 93 unrelated individuals who had suffered one or more concussions were recruited to the study. Index cases were collected through four avenues:\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cem\u003en =\u0026nbsp;\u003c/em\u003e15 cases that had developed severe reactions to trivial head trauma and referred for FHM gene testing, but negative for pathogenic variants in known genes. Their clinical presentations and DNA collection have been described previously\u0026nbsp;[39]. Sample identification (ID) numbers: R#.\u003c/li\u003e\n \u003cli\u003e\u003cem\u003en =\u0026nbsp;\u003c/em\u003e11 participants were recruited through Brisbane hospitals with diagnosed concussion. Sample IDs: BBB#.\u003c/li\u003e\n \u003cli\u003e\u003cem\u003en =\u0026nbsp;\u003c/em\u003e32 participants were recruited through local sporting groups and campus recruitment. Of these, 21 had concussion diagnosed by a medical professional and the remainder are self-reported. Twenty reported multiple concussions in the collected questionnaire data. Sample IDs: C#, CN#.\u003c/li\u003e\n \u003cli\u003e\u003cem\u003en =\u003c/em\u003e 35 Australian Defence Force veterans who had previously sustained concussion/s were recruited through the Gallipoli Medical Research Foundation - Greenslopes Private Hospital (GMRF-GPH) Biobank. Sample IDs: P#.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eResponse to concussion in the participants varied from no severe or long-lasting symptoms to persistent and ongoing symptoms including migraine, memory problems, fatigue, and vertigo from 3 months to \u0026gt;1 year post concussion event. Available information related to participant\u0026rsquo;s concussion history and symptoms is provided in Supplementary Table 1. For some cases family members were also recruited (n=15).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDNA extraction and Whole Exome Sequencing\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenomic DNA was isolated from either whole blood samples using QIAamp DNA Blood Mini Kits (Qiagen, Hilden, Germany), or from saliva using ORAgene-DNA OG-500 kits and PrepIT reagent (DNA Genotek, Stittsville, Canada) as per the manufacturer\u0026apos;s instructions. We have previously shown that results for WES using DNA obtained from either blood or saliva is comparable [40]. Extracted blood DNA samples were available from the GMRF-GPH Biobank samples.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNext-generation sequencing libraries for WES were constructed using Ion AmpliSeqTM Exome RDY Library Kits (Cat. no. 4489837 Rev A.0, Thermo Fisher, Scoresby, VIC, Australia) according to the manufacturer\u0026apos;s protocol. The libraries were sequenced on the Ion S5 plus sequencer, using Ion v550 Chips (Thermo Fisher Scientific, Carlsbad, Ca., USA). Sequence reads were aligned to the human reference genome (hg19), the variants were called and the VCF files were generated using the Ion Torrent Suite software (Thermo Fisher Scientific, Carlsbad, Ca., USA). \u0026nbsp;The VCF files were then uploaded to the locally hosted Ion Reporter Server software (v5.12) for automated variant annotation and filtering. The Binary Alignment/Map (BAM) bam format files were uploaded into the Integrative Genomics Viewer (IGV v2.3) software (http://www.broadinstitute.org/igv), to visually examine potential variants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eVariant Curation\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTiered analysis of WES data was performed to explore rare genetic variants in relevant genes. Exome variants were filtered for analysis to identify variants in genes i) causally implicated in severe types of migraine \u003cem\u003e(CACNA1A, ATP1A2,\u0026nbsp;\u003c/em\u003eand \u003cem\u003eSCN1A)\u003c/em\u003e; ii) ion channel and transporter genes (\u003cem\u003en\u003c/em\u003e = 353 genes); and iii) genes affecting neurotransmission (\u003cem\u003en\u003c/em\u003e = 220 genes) selected using the following gene ontologies: neural, neurological, brain, ion channel, and neuro* - Gene Ontology 20171101 (Tier 1-3, respectively). Gene lists for ion channel and neurotransmitter-related genes are in Supplementary Table 2. The three tiers of analysis were performed through Ion Reporter v5.12 filtering (Thermo Fisher).\u003c/p\u003e\n\u003cp\u003eIdentified variants were then filtered to include only variants that i) affected amino-acid composition of the protein; ii) had minor allele frequency (MAF) \u0026lt;0.02 in the gnomAD NFE cohort c2.1.1 (exomes); iii) were predicted to be damaging by two or more \u003cem\u003ein silico\u003c/em\u003e analysis tools (SIFT version 5.2.2 [41]; PolyPhen version 2.2.2 release 405c [42]; MutationTaster2021 [43]; CADD score based upon Ensembl Ch37 [44]); iv) passed visual confirmation in IGV (v2.5.3); v) in genes with variants identified in multiple (two or more) unrelated patients. A post hoc manual selection was then undertaken based on literature and known biological relevance. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGenotyping of selected variants in a migraine case-control cohort\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess frequencies of the channel-related variants detected in the concussion cohort in independent samples some genes/variants of interest in \u003cem\u003eATP7B\u003c/em\u003e, \u003cem\u003eCACNB2\u003c/em\u003e, \u003cem\u003eSCN8A\u003c/em\u003e, \u003cem\u003eSCN9A\u003c/em\u003e, and \u003cem\u003eSCN10A\u003c/em\u003e were prioritised for genotyping in an Australian cohort of 280 migraine cases and 280 sex- and age-matched controls. Genotyping was performed via a multiplex MassARRAY assay (Agena Bioscience, San Diego, CA, USA). Primers were designed using Assay Design Suite v3.0 software for: \u003cem\u003eATP7B\u003c/em\u003e variants c.122A\u0026gt;G (p.Asn41Ser), c.1555G\u0026gt;A (p.Val519Met), c.2383C\u0026gt;T (p.Leu795Phe), c.2972C\u0026gt;T (p.Thr991Met), c.3700G\u0026gt;T (p.Val1234Phe), and c.3859G\u0026gt;A (p.Gly1287Ser); \u003cem\u003eCACNB2\u0026nbsp;\u003c/em\u003evariants c.503G\u0026gt;A (p.Cys168Tyr) and c.1357C\u0026gt;T (p.Leu453Phe); \u003cem\u003eSCN8A\u003c/em\u003e variant c.3076C\u0026gt;T (p.Arg1026Cys), \u003cem\u003eSCN9A\u003c/em\u003e variants c.684C\u0026gt;G (p.Ile228Met), c.1109C\u0026gt;T (p.Thr370Met), c.3734A\u0026gt;G (p.Asn1256Ser) and c.3799C\u0026gt;G (p.Leu1278Val); and \u003cem\u003eSCN10A\u003c/em\u003e variants c.2530C\u0026gt;T (p.Arg844Cys), c.3859G\u0026gt;A (p.Val1287Ile), and c.4585G\u0026gt;A (p.Ala1529Thr). Sequences available upon request. Not all variants of interest were genotyped due to assay designability or cost constraints. Primers were obtained from Integrated DNA Technologies (Singapore). Genotyping was conducted according to manufacturer\u0026rsquo;s protocols using PCR and iPLEX MassARRAY reagents on a matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry platform (Agena Biosciences, San Diego, CA, USA). Genotypes were called with Typer 4.0 software. Assays for \u003cem\u003eSCN9A\u003c/em\u003e p.Ile228Met and \u003cem\u003eSCN10A\u003c/em\u003e p.Val1287Ile variants failed and were not further analysed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRare Variant Burden Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRare variant burden analysis focused on the rare variants identified in the known FHM genes and other ion channel genes reported in this study. Counts of these variants were compared with the numbers observed in a general population control group obtained from the gnomAD database, selecting non-Finnish Europeans as most similar to the ancestral background of the recruitment population in Australia, using a Fisher\u0026apos;s Exact test to determine statistical significance. Odds ratios were calculated as an estimate of effect size.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003eSingle Variant analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnnotated WES data from 93 unrelated individuals that have sustained one or more concussions was filtered to focus on rare (MAF \u0026lt;0.02), protein coding variants in known causative migraine genes, ion channel genes, or genes affecting neurotransmission (Supplementary Table 2) in accordance with our hypothesis that genetic vulnerabilities in these genes contribute to increased concussion risk. Rare amino acid changing variants that were predicted to be damaging according to at least two of the \u003cem\u003ein silico\u003c/em\u003e prediction tools used were identified. 61.5% of these were predicted damaging by all four tools. In total, 62 rare missense variants were identified across 24 genes in 59 (63%) participants, with 26 participants harboring two or more candidate variants. All identified variants were heterozygous in participants. Tables 1, 2 and 3 detail the 62 variants identified in the three tiers of analysis: i) known migraine causative genes; ii) ion channel and transporter genes; and iii) genes affecting the neurotransmission, respectively, and include results of \u003cem\u003ein silico\u003c/em\u003e predictions, summaries of current ClinVar classifications, and the gnomAD MAF for each in non-Finnish Europeans. Genes carrying identified variants included calcium channels (\u003cem\u003eCACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1I, CACNB2\u003c/em\u003e), sodium channels (\u003cem\u003eSCN1A, SCN8A, SCN9A, SCN10A\u003c/em\u003e), ATPases (\u003cem\u003eATP10A, ATP13A4, ATP7B\u003c/em\u003e), potassium channels (\u003cem\u003eKCNJ10, KCNT2\u003c/em\u003e) and various genes involved in neurotransmission (\u003cem\u003eCHAT, DAGLB, KIF17, NRG1, SNCAIP, SV2C, SYT9, UNC13B\u003c/em\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe genes carrying most variants across the cohort were: \u003cstrong\u003e\u003cem\u003eSNCAIP\u003c/em\u003e\u003c/strong\u003e with four variants found across 10 participants including p.Glu709Gln in five participants and p.Arg806His in three participants; \u003cstrong\u003e\u003cem\u003eSCN9A\u003c/em\u003e\u003c/strong\u003e with six variants identified across seven participants, including p.Asn1256Ser identified in three participants and one participant carrying two potentially damaging variants p.Leu1278Val and p.Ile228Met; \u003cstrong\u003e\u003cem\u003eATP7B\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ewith six variants across six participants; \u003cstrong\u003e\u003cem\u003eCHAT\u003c/em\u003e\u003c/strong\u003e with three variants identified in six participants including p.Arg561Gln in three participants; \u003cstrong\u003e\u003cem\u003eKIF17\u003c/em\u003e\u003c/strong\u003e with three variants across four participants, including p.Arg111Gly in two participants;\u003cstrong\u003e\u003cem\u003e\u0026nbsp;SCN8A\u003c/em\u003e\u003c/strong\u003e with the p.Arg1026Cys variant present in four participants; \u003cstrong\u003e\u003cem\u003eSYT9\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ewith two variants across four participants, including p.Leu353Val identified in three participants; \u003cstrong\u003e\u003cem\u003eCACNA1A\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ewith one variant, p.Ala454Thr identified in three participants; and \u003cstrong\u003e\u003cem\u003eSCN10A\u003c/em\u003e\u003c/strong\u003e with four variants across four participants. Some related individuals were available to look at segregation of variants in family members (Supplementary Tables 3 and 4), although, limited by small pedigrees and the fact that some kind of head trauma is required to be considered a case, we were unable to reach any strong conclusions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFifteen variants identified in the concussion cohort were further genotyped in a migraine case-control cohort of 280 migraine cases and 280 age- and sex-matched controls via an Agena MassARRAY plex to confirm their frequency in a population collected from a similar geographical background, or with some symptomatic overlap (i.e. migraine). As results presented in Table 4 show, the channel variants identified in the concussion cohort were confirmed to be rare in general populations, and they do not appear to be particularly associated with migraine which is a common symptom of concussion.\u003c/p\u003e\n\u003cp\u003eAlthough all the variants we identified were predicted to be deleterious, there is insufficient evidence to suggest that any are pathogenic in a monogenic autosomal dominant manner, as the participant\u0026rsquo;s symptoms of concussion were precipitated with head trauma. However, the results suggest that variants across ion channels and neurotransmitter genes that may be sub-clinical could plausibly confer increased susceptibility to concussion and exacerbate post injury ionic fluxes post-TBI under limited energy/recovery conditions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRare variant burden analysis on ion channel genes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRare variant burden analysis focusing on the variants identified in the 16 ion channel genes from the Tier 1 and 2 analyses (Tables 1 and 2) was conducted to test whether there was enrichment (increased prevalence) of the damaging variants identified in the ion channel gene set in the concussion participants compared to a general population control group obtained from the gnomAD database (non-Finnish Europeans). As detailed in Supplementary Table 5, in our concussion cohort we identified 43 different rare, amino acid changing variants in 16 ion channel and ion channel transporter genes, according to our filtering criteria. The overall prevalence of damaging alleles was rare (\u0026lt;0.02) in both the case and control groups. In the concussion group, a total of 51 predicted damaging alleles at these loci were observed. This prevalence (0.64%) was ~5-fold greater than the prevalence of these alleles observed in the gnomAD population control group (0.12%) and significantly different by Fisher\u0026rsquo;s Exact test (Odds Ratio = 5.44, CI: 4.13, 7.18; P \u0026lt; 0.0001). Gene-based burden testing was not conducted due to the limited size of the concussion cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Details of rare genetic variants identified in known migraine causative genes\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"983\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" valign=\"bottom\" style=\"width: 543px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant details\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 213px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBioinformatic predictions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGnomAD NFE data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRef\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmino Acid Change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoding change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSNP ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCLINVAR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSamples with Variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIFT pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePolyphen2 HDIV pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutation\u003cbr\u003e\u0026nbsp;Taster pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCADD phred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant Allele\u003cbr\u003e\u0026nbsp;count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Allele count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFreq\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNA1A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e19:13428124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ala454Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003ec.1360G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ers41276886\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003elikely benign (14) \u0026ndash; Condition: Various neurological disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN7\u003c/p\u003e\n \u003cp\u003eP034\u003c/p\u003e\n \u003cp\u003eP038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e24.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e265\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e47808\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.005543\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN1A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:166848003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1917Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003ec.5749C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003ca href=\"http://www.ncbi.nlm.nih.gov/snp/rs121917956\"\u003ers121917956\u003c/a\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003elikely benign (12) \u0026ndash; Condition: Various neurological disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN11\u003c/p\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e22.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e48282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001388\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGnomAD NFE = allele frequency of non-Finnish Europeans, GnomAD allele count is based upon v2.1.1 (exomes).\u003c/p\u003e\n\u003cp\u003eSIFT is based on version 5.2.2; PolyPhen is based on version 2.2.2 release 405c; MutationTaster2021; CADD score is based upon Ensembl Ch37.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Details of rare genetic variants identified in ion channel and ion transporter genes\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"987\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" valign=\"bottom\" style=\"width: 543px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant details\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 216px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBioinformatic predictions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGnomAD NFE data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRef\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmino Acid Change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoding change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSNP ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCLINVAR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSamples with Variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIFT pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePolyphen2 HDIV pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutation\u003cbr\u003e\u0026nbsp;Taster pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCADD phred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant Allele\u003cbr\u003e\u0026nbsp;count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Allele count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFreq\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eATP10A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e15:25947181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ala881Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2642C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers142704035\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR170\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e32\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e15:26108002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Glu81Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.242A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers368768805\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e24.7\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e107790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000102\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eATP13A4\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:193132450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asn978His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2932A\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers770185624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e22.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eATP7B\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13:52511656\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Gly1287Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3859G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers762866453\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (6) relating to Wilson Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP254\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e27.6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113286\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13:52511815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Val1234Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3700G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers193922108\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e33\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13:52520508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Thr991Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2972C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers41292782\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (9) relating to Wilson Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eC4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e33\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.002359\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" rowspan=\"2\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13:52531716\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Leu795Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2383C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers751710854\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003ePathogenic/Likely pathogenic (9) relating to Wilson Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR211\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e28.3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13:52542732\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Val519Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1555G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers192957846\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (5) relating to Wilson disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN25\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e29.3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001123\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13:52549234\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asn41Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.122A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers201738967\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003ePathogenic/Likely pathogenic (12) relating to Wilson Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e24.4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000486\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNA1B\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e9:140952560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1389His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.4166G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers184841813\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eBBB19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000690\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e9:141015296\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ser2151Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.6452C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers200034261\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP235\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e29.9\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e75310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000491\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNA1C\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e12:2690844\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ile662Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1984A\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR259\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e23.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e12:2774859\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Tyr1552Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.4655A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers2153709630\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (1) \u0026ndash; Condition: Long QT Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eC5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e32.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e12:2800220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asn2174Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.6521A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers201090446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eBBB12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e24.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e104020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000663\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNA1D\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:53787624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asn1254Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3761A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers147146258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP186\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e22.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113768\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000686\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:53837487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1845Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.5533C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers144688228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (3) \u0026ndash; Condition: not Provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e23.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113770\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000149\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:53844173\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Gly2034Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.6100G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers368340190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (1) \u0026ndash; Condition: not Provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e20.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113558\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNA1E\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:181706777\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ser1180Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3539C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers202226007\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:181759588\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1932Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.5794C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers776416674\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eBBB12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e26.8\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112858\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:181767528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg2167Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.6500G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers370385055\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (2) \u0026ndash; Condition: not Provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112966\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNA1I\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e22:40045653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ser537Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1610C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers372904212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP191\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e22.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e44670\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000134\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e22:40081856\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asp2005Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.6013G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers771105041\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP186\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eN\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e29.4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e27346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001536\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e22:39994250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg111Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.331C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers751729397\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR211\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e103132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNB2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10:18789787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Cys168Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.503G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers773215003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (4) \u0026ndash; Condition: various cardiovascular conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e26.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10:18827118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asp438Asn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1312G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers778466195\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (2) \u0026ndash; Condition: cardiovascular phenotype and Brugada syndrome 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113742\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10:18827163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Leu453Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1357C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers145638628\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (4) \u0026ndash; Condition: cardiovascular phenotype and Brugada syndrome 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e29.0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113762\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000422\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eKCNJ10\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:160011262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Lys354Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1061A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers142596580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (9) \u0026ndash; Condition: Condition: various including EAST syndrome and non-syndromic hearing loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e26.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113678\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000475\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:160012271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg18Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.52C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers138457635\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain Significance (7) \u0026ndash; Condition: Condition: various including EAST syndrome and non-syndromic hearing loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR117\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e27.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113716\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000686\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eKCNT2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:196250115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Lys929Glu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2785A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers1659036452\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e22.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:196309627\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ile543Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1627A\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers780602272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN9A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:167089942\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Leu1278Val\u003c/p\u003e\n \u003cp\u003e(p.Leu1267Val)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3832C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers180922748\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (16) \u0026ndash; Condition: Various including pain and seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e26.5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e102260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.002073\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:167094638\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asn1256Ser\u003c/p\u003e\n \u003cp\u003e(p.Asn1245Ser)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3767A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers141268327\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (24) \u0026ndash; Condition: Various including pain and seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR211\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eP026 R171\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e23.9\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e837\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e111518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.007506\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:167108386\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1121Trp\u003c/p\u003e\n \u003cp\u003e(p.Arg1110Trp)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3361C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers190664764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (6) \u0026ndash; Condition: \u0026nbsp;pain and seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eR256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e24.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001479\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:167137020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Trp730Cys\u003c/p\u003e\n \u003cp\u003e(p.Trp719Cys)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2190G\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers202055175\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (15) \u0026ndash; Condition: \u0026nbsp;pain and seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eBBB7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e91662\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:167145152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Thr370Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.1109C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers200391162\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (5) \u0026ndash; Condition: \u0026nbsp;pain and seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eBBB27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e32\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e102700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2:167160752\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ile228Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.684C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers71428908\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (16) \u0026ndash; Condition: \u0026nbsp;pain and seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e22.8\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001716\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN10A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:38743402\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ala1529Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.4585G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers757916036\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP232\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113512\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:38753882\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Val1287Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3859G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers145032037\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113524\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:38755450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1268Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3803G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers138832868\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (7) \u0026ndash; Conditions: pain disorders and cardiovascular phenotypes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eBBB3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e25.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e313\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113532\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.002757\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3:38770143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg844Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.2530C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers140158387\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eUncertain significance (2) - Conditions: Cardiovascular phenotypes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e35\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113548\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN8A\u003c/em\u003e\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e12:52162823\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg1026Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ec.3076C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ers117217073\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eConflicting classifications of pathogenicity (6) \u0026ndash; Condition: seizure disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCN18\u003c/p\u003e\n \u003cp\u003eR167 BBB15 P194 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 46px;\"\u003e\n \u003cp\u003e24.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1663\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.014730\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGnomAD NFE = allele frequency of non-Finnish Europeans, GnomAD allele count is based upon v2.1.1 (exomes).\u003c/p\u003e\n\u003cp\u003eSIFT is based on version 5.2.2; PolyPhen is based on version 2.2.2 release 405c; MutationTaster2021; CADD score is based upon Ensembl Ch37.\u003c/p\u003e\n\u003cp\u003e* Variant has previously been described in the literature with alternate protein residue number as annotated against a different transcript.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eR170 A rare variant in \u003cem\u003eATP10A\u003c/em\u003e was previously reported in Ibrahim et al (2020) [39].\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eR211 Rare variants in \u003cem\u003eATP7B\u003c/em\u003e and \u003cem\u003eCACNA1I\u003c/em\u003e were previously reported in Ibrahim et al (2020).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e R259 Rare variant in \u003cem\u003eCACNA1C\u003c/em\u003e was previously reported in Ibrahim et al (2020).\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003e R117 Rare variant in \u003cem\u003eKCNJ10\u003c/em\u003e was previously reported in Ibrahim et al (2020).\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ee\u003c/sup\u003e R171 also carries a rare variant in \u003cem\u003eGRIK1\u003c/em\u003e that is predicted to be deleterious as previously reported in Ibrahim et al (2020), not listed here as no other sample in this cohort carries a rare, potentially deleterious variant in this gene.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ef\u003c/sup\u003e Some regions of the \u003cem\u003eSCN8A\u003c/em\u003e gene have poor WES coverage with Ion AmpliSeqTM Exome Kits, so some variants in this gene may be missed.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Details of genetic variants identified in neurotransmission-related genes\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"988\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" valign=\"bottom\" style=\"width: 541px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant details\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBioinformatic predictions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGnomAD NFE data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRef\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmino Acid Change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoding change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSNP ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCLINVAR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSamples with Variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIFT pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePolyphen2 HDIV pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutation\u003cbr\u003e\u0026nbsp;Taster pred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCADD phred\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant Allele\u003cbr\u003e\u0026nbsp;count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Allele count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFreq\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eCHAT\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10:50835688\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg323His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.968G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers200176236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eLikely Benign (1) \u0026ndash; Condition: familial infantile mysathenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN41\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113718\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000255\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10:50856643\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Leu458Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1372C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers76014951\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBenign/Likely Benign (6) \u0026ndash; Condition: familial infantile mysathenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN32 P191 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e26.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e569\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112684\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.005050\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10:50863188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg561Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1682G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers80097077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBenign/Likely Benign (7) \u0026ndash; Condition: familial infantile mysathenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN11\u003c/p\u003e\n \u003cp\u003eBBB3\u0026nbsp;R118\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e27.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.010460\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eDAGLB\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e7:6449794\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ile596Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1787T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers139753251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBenign (1) \u0026ndash; Condition: Not provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN26 P242 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e25.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e896\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e94702\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.009461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eKIF17\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:21009189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Glu807Ala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.2420A\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers115257742\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN32\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e28.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113682\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001654\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:21042033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg111Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.331A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers35835983\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN6\u003c/p\u003e\n \u003cp\u003eBBB17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1966\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113480\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.017320\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1:21044007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Glu65Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.193G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers147438943\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e24.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e709\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e110288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.006429\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eNRG1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e8:32617888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Thr416Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1247C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers62497784\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eLikely Benign (1) \u0026ndash; Condition: Not provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eBBB17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e22.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.003576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSNCAIP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5:121759069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Val213Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.637G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers201152226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eP095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e17.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5:121786403\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg621Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1861C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers28937592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eLikely Benign (4) \u0026ndash; Condition: Parkinson disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eP160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e27.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113618\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.005457\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5:121786667\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Glu709Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.2125G\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers55712196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eLikely Benign (3) \u0026ndash; Condition: Parkinson disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN28 C4 R222 P194 P178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e24.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1418\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113392\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.012510\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5:121786959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg806His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.2417G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers140850272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBenign (2) \u0026ndash; Condition: Parkinson disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eR259 P027 P202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e28.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113672\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.013650\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSV2C\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5:75581035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Val321Glu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.962T\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers762537711\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eP186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e29.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000026\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5:75591631\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asp456Asn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1366G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers756018103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eC7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e25.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e112560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eSYT9\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e11:7324378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg85Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.254G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers773842068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eR211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e24.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e11:7437285\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Leu353Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.1057C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers117876446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN1 P202 P200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113672\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.009774\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eUNC13B\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e9:35380598\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Arg697Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.2090G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers144007866\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eP194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000255\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e9:35381587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Ser760Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.2279G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers911067546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eR150\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e20.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e9:35396516\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ep.Asn1035Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ec.3105C\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003ers918241456\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003eCN29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e22.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e113586\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGnomAD NFE = allele frequency of non-Finnish Europeans, GnomAD allele count is based upon v2.1.1 (exomes)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSIFT is based on version 5.2.2; PolyPhen is based on version 2.2.2 release 405c; MutationTaster2021; CADD score is based upon Ensembl Ch37\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e R118 also carries a rare variant in \u003cem\u003eKCNAB1\u003c/em\u003e that is predicted to be deleterious as previously reported in Ibrahim et al (2020) [39], although not listed here as no other sample in this cohort carries a rare, potentially deleterious variant in this gene.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eR150 also carries a rare variant in \u003cem\u003eGABRG1\u003c/em\u003e that is predicted to be deleterious as previously reported in Ibrahim et al (2020), not listed here as no other sample in this cohort carries a rare, potentially deleterious variant in this gene.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003c/strong\u003e\u003cstrong\u003eTable 4:\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eGenotypic analysis of ion channel variants identified in concussion study in general migraine case-control cohort\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"631\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eVariant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003egnomAD MAF (NFE)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. variant alleles in migraine cases (n=280) / Frequency*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. variant alleles in controls (n=280) /\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFrequency*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cem\u003eATP7B\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Asn41Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Val519Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.001123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1 / 0.00179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Leu795Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Thr991Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.002359\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e2 / 0.00357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e3 / 0.00536\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Val1234Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Gly1287Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cem\u003eCACNB2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Cys168Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Leu453Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1 / 0.00179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e1 / 0.00179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN8A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Arg1026Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.014730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e2 / 0.00357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e7 / 0.0125\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN9A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Thr370Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Asn1256Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.007506\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1 / 0.00179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Leu1278Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.002073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1 / 0.00179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCN10A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Arg844Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Val1287Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.001110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.Ala1529Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.000009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* \u0026nbsp;If number (no.) of variant alleles is \u0026gt;0.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eExploring the hypothesis that rare genetic variation across known causative migraine genes, ion channels and neurotransmission-related genes may contribute to\u0026nbsp;an increased vulnerability to concussion, we found that 63% of participants who had sustained concussion carried at least one rare, potentially deleterious (based on \u003cem\u003ein silico\u003c/em\u003e prediction) missense heterozygous variant in an ion channel or neurotransmitter-related gene. Furthermore, many of the prioritised genes bore variants in multiple unrelated cases, with eight genes carrying variants identified in four or more participants. Combined, the data identifies genes with plausible involvement in concussion susceptibility and suggests the need for further investigation of the functional effects of the observed variants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFamilial hemiplegic migraine genes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCausal genes for FHM – \u003cem\u003eCACNA1A\u003c/em\u003e (FHM1), \u003cem\u003eATP1A2\u003c/em\u003e (FHM2), or \u003cem\u003eSCN1A\u003c/em\u003e (FHM3) – were specifically included in the analysis due to the symptomatic overlap of these disorders with the neurologic symptoms that often present after concussion and the\u0026nbsp;dysregulation of ion fluxes and neurotransmission that occurs in both migraine and concussion patients.\u0026nbsp;We had previously found that a high proportion (35%) of hemiplegic migraine cases with pathogenic \u003cem\u003eATP1A2\u003c/em\u003e missense variants were noted to have incidence of concussion or concussion-related symptoms after mild head trauma [45]. These individuals had been excluded from the current study and no further rare \u003cem\u003eATP1A2\u003c/em\u003e variants were identified in this cohort.\u003c/p\u003e\n\u003cp\u003eFHM patients with \u003cem\u003eCACNA1A\u003c/em\u003e mutations may also be highly sensitive to head impacts [34,35]. Three unrelated participants had a rare missense variant (p.Ala454Thr) in \u003cem\u003eCACNA1A\u003c/em\u003e, which encodes the pore-forming subunit of the voltage-gated calcium channel Ca\u003csub\u003eV\u003c/sub\u003e2.1 [46] and plays an important function in controlling neurotransmitter release at presynaptic terminals [47-49]. p.Ala454Thr is likely benign in ClinVar, although was previously found in a heterogeneous ataxic disorder [50] and shown to confer loss-of-function (LoF) effects, altering the voltage dependence of steady-state inactivation and interactions between Cav2.1 and SNARE proteins leading to a decreased channel coupling to exocytosis\u0026nbsp;[51]. Such functional effects could potentially contribute to dysregulation of the ion fluxes that occur in concussion.\u003c/p\u003e\n\u003cp\u003eA p.Arg1917Gly variant in \u003cem\u003eSCN1A\u003c/em\u003e, which encodes the voltage-gated sodium channel Na\u003csub\u003eV\u003c/sub\u003e1.1, was identified in two unrelated participants. Notably both participants also have a second rare missense variant in other genes of interest, i.e. \u003cem\u003eCHAT\u003c/em\u003e (C2) or \u003cem\u003eCACNB2\u0026nbsp;\u003c/em\u003e(CN11). Although \u003cem\u003eSCN1A\u003c/em\u003e p.Arg1917Gly is classified as likely benign in ClinVar, participant CN11 reported multiple concussions with ongoing photo- and phono-sensitivity and migraine with aura (age of onset 30 years).\u0026nbsp;We therefore suggest that while this heterozygous variant may not lead to the severe FHM phenotype under normal conditions, head trauma may act as a precipitant of disturbance leading to the migraine with aura phenotype post-concussion, with or without additional variant burden in other ion channel or neurotransmission related genes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIon channel genes and ion transporter genes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn expanded analysis of a panel of 353 ion channel and related genes identified potential causal variants in other ion channel genes in concussion cases. Rare variants were detected in genes encoding\u0026nbsp;calcium channel\u0026nbsp;a1 (\u003cem\u003eCACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1I\u003c/em\u003e) and auxiliary subunits\u003cem\u003e\u0026nbsp;\u003c/em\u003e(\u003cem\u003eCACNB2\u003c/em\u003e), sodium channel\u0026nbsp;a1 subunits (\u003cem\u003eSCN1A, SCN8A, SCN9A, SCN10A\u003c/em\u003e), ATPases (\u003cem\u003eATP7B\u003c/em\u003e, \u003cem\u003eATP10A, ATP13A4\u003c/em\u003e), and potassium channel subunits (\u003cem\u003eKCNJ10, KCNT2\u003c/em\u003e).\u0026nbsp;The highest number of damaging rare variants in ion channel-related genes was detected in \u003cem\u003eSCN9A\u003c/em\u003e (i.e. six different variants in eight cases).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCalcium channel genes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCellular calcium influx is a key component of the neurometabolic cascade following a deceleration injury as highlighted by Giza and Hovda [24]. “\u003cem\u003eCACNA1x\u003c/em\u003e” are a family of conserved genes that code the 10 different pore‐forming α1 subunits of voltage‐gated calcium channels (VGCCs). Including \u003cem\u003eCACNA1A\u003c/em\u003e discussed previously, 18 rare variants were identified across seven VGCCs, with three participants carrying two missense variants in two different calcium channel genes (BBB12—\u003cem\u003eCACNA1C\u003c/em\u003e p.Asn2174Ser and \u003cem\u003eCACNA1E\u003c/em\u003e p.Arg1932Trp; P186—\u003cem\u003eCACNA1I\u003c/em\u003e p.Asp2005Tyr and \u003cem\u003eCACNA1D\u003c/em\u003e p.Asn1254Ser; and P200—\u003cem\u003eCACNA1E\u003c/em\u003e p.Ser1180Leu and \u003cem\u003eCACNB2\u003c/em\u003e p.Cys169Tyr).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThree rare variants were identified in \u003cem\u003eCACNA1I\u003c/em\u003e. The p.Arg111Gly variant in R211, who had severe migraine and ataxia following head injury and a family history of migraine, had been previously reported [39]. Functional testing of p.Arg111Gly variant Ca\u003csub\u003eV\u003c/sub\u003e3.3 channels by patch-clamp assay found that it reduced current density in comparison with wild-type [52]. The other two \u003cem\u003eCACNA1I\u003c/em\u003e variants identified in unrelated cases should be considered for similar functional follow-up. The \u003cem\u003eCACNA1B\u003c/em\u003e p.Arg1389His variant found in BBB19 has previously been linked to dystonia, albeit with conflicting results [53,54]. Functional analysis of this variant in a study of a family with myoclonus-dystonia syndrome with cardiac arrhythmias showed that mutant channels carried less current when open compared with wild-type Ca\u003csub\u003eV\u003c/sub\u003e2.2 channels, consistent with a gain-of-function (GoF)\u0026nbsp;[53].\u003c/p\u003e\n\u003cp\u003eThree variants each were found in nine different participants in the \u003cem\u003eCACNA1C, CACNA1D,\u0026nbsp;\u003c/em\u003eand \u003cem\u003eCACNA1E\u0026nbsp;\u003c/em\u003egenes, which encode the a1 subunits of Ca\u003csub\u003eV\u003c/sub\u003e1.2, Ca\u003csub\u003eV\u003c/sub\u003e1.3, and Ca\u003csub\u003eV\u003c/sub\u003e2.3 channels, respectively, which have important roles in a variety of neuronal processes [55]. \u003cem\u003eCACNA1C\u003c/em\u003e has been associated with a spectrum of cardiac and neurological disorders including Timothy Syndrome [56]. The \u003cem\u003eCACNA1C\u003c/em\u003e p.Asn2174Ser variant (also annotated as p.Asn2091Ser in some transcripts) has been previously identified in a case of sudden unexplained death in the young (SUDY) and shown to exhibit minor kinetic alterations in functional tests [57]. \u003cem\u003eCACNA1D\u003c/em\u003e, expressed in post-synaptic neurons, is associated with increased risk of neuropsychiatric disease and epilepsy [58], while \u003cem\u003eCACNA1E\u003c/em\u003e Ca\u003csub\u003eV\u003c/sub\u003e2.3 channels initiate rapid synaptic transmission through high-voltage-activated, rapidly inactivating R-type calcium currents in the central nervous system (CNS), with \u003cem\u003ede novo\u003c/em\u003e missense \u003cem\u003eCACNA1E\u003c/em\u003e variants causal for developmental and epileptic encephalopathies [59].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSodium channel genes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSodium channels are also involved in a variety of neurological disorders including migraine, epilepsy, and pain disorders. Furthermore, increasing evidence suggests that concussion can induce forms of sodium channelopathy [60,29]. The detection of multiple variants in this class of genes in individuals that had sustained concussion may indicate that vulnerability to, or more severe reactions to concussion, could arise from functional variants which effect regulation of sodium ion fluxes.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSCN9A\u003c/em\u003e encodes the voltage-gated sodium channel subunit Na\u003csub\u003eV\u003c/sub\u003e1.7 which plays a significant role in nociception signaling and pain mechanisms. Pathogenic GoF variants in \u003cem\u003eSCN9A\u003c/em\u003e that affect neuronal excitability have been associated with varying clinical presentations, including primary erythromelalgia, paroxysmal extreme pain disorders, and peripheral neuropathy [61-63]. \u003cem\u003eSCN9A\u003c/em\u003e variants have also been associated with various epilepsy and seizure disorders [64,65]. Six rare missense mutations at residues highly conserved across mammalian orthologues were identified in the \u003cem\u003eSCN9A\u003c/em\u003e gene across the concussion cohort, four of which have been previously associated with known pain-related disorders [63,66]. \u003cem\u003eSCN9A\u003c/em\u003e p.Ile228Met\u0026nbsp;has been functionally shown to impair slow-inactivation (i.e. GoF) and can increase the excitability of trigeminal and dorsal root ganglion neurons\u0026nbsp;[66,67]. Estacion and colleagues identified the variant in the three patients showing phenotypic diversity of pain disorders—one primary erythromelalgia, and two with small fibre neuropathy\u0026nbsp;[66]. Participant CN10 with the p.Ile228Met variant reported a single concussion with ~18 months recovery time, however, suffered ongoing mental fatigue, visual disturbances, and occasional memory disturbances. Interestingly, they\u0026nbsp;also have a \u003cem\u003eSCN9A\u003c/em\u003e p.Leu1278Val variant. \u003cem\u003eSCN9A\u003c/em\u003e variants including\u0026nbsp;p.Leu1278Val have been found in Dravet syndrome patients alongside \u003cem\u003eSCN1A\u003c/em\u003e mutations; Singh et al. hypothesised that\u0026nbsp;carriers of \u003cem\u003eSCN9A\u003c/em\u003e variants might be asymptomatic or present with infrequent febrile seizures due to incomplete penetrance and variable expressivity, but have a modifier effect when combined with \u003cem\u003eSCN1A\u003c/em\u003e variants in Dravet syndrome, contributing to the variable presentation\u0026nbsp;[64].\u0026nbsp;The \u003cem\u003eSCN9A\u003c/em\u003e p.Asn1256Ser variant was found in three different participants reporting confusional migraine or migraine-like episodes following head injury. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003eSCN8A\u003c/em\u003e p.Arg1026Cys variant was present in four unrelated participants, an allele frequency of 2.2% in this cohort, while at ~1.4% in general population databases. \u003cem\u003eSCN8A\u003c/em\u003e encodes the voltage-gated sodium channel subunit Na\u003csub\u003eV\u003c/sub\u003e1.6, and pathogenic variants can be classed as either LoF or GoF with variable consequences. Pathogenic GoF variants generally present with early-infantile epilepsies, while LoF variants generally lead to later-onset epilepsies, absence epilepsy, neurodevelopmental delays, and behavioral features such as attentional dysfunction [68,69]. Interestingly, a swine model that had undergone experimental concussion showed widespread loss of Na\u003csub\u003eV\u003c/sub\u003e1.6 channel isoforms in white matter axons at 6 h and 72 h after injury, which recovered by two weeks post-injury, and may underlie the brain network dysfunction that occurs after concussion [29]. A loss of Na\u003csub\u003eV\u003c/sub\u003e1.6 and changes in nodes of Ranvier structures were similarly observed in the white matter of post-mortem human brain samples with TBI [29].\u003c/p\u003e\n\u003cp\u003eFour different rare \u003cem\u003eSCN10A\u003c/em\u003e missense variants in four concussion participants were identified. \u003cem\u003eSCN10A\u003c/em\u003e encodes a neuronal voltage-gated sodium channel subunit of Na\u003csub\u003eV\u003c/sub\u003e1.8, an important regulator of neuronal excitability. \u003cem\u003eSCN10A\u003c/em\u003e pathogenic variants are most commonly associated with cardiac disorders [70], but also have been associated with cases of autism spectrum disorder [71,72], pain perception and seizures [73], and small fibre neuropathy [63].\u003c/p\u003e\n\u003cp\u003eSome of the sodium channels variants we detected have previously been shown to have clinical relevance and/or functional effects. We hypothesize that the variants may contribute to minor effects on sodium channel function, which, in the event of trauma, are sufficient to interfere with normal neuronal function and homeostasis. The finding of multiple rare and potentially damaging variants in sodium channel genes in our concussion cohort aligns with the proposal that sodium channelopathy underlies concussion symptoms [29,60]. Our results could be particularly relevant in cases of multiple concussions to the finding that traumatic axonal injury from concussion induces a form of sodium channelopathy on axons that greatly exaggerates the pathophysiologic response to subsequent mild injuries [60].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eATPase genes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThree ATPase related genes with multiple rare variants were identified in the study: \u003cem\u003eATP10A\u003c/em\u003e (\u003cem\u003en\u003c/em\u003e = 2 variants), \u003cem\u003eATP13A4\u003c/em\u003e (\u003cem\u003en\u003c/em\u003e = 1 variant, also present in an affected family member, Supplementary Table 4), and \u003cem\u003eATP7B\u003c/em\u003e (\u003cem\u003en\u003c/em\u003e = 6 variants). The \u003cem\u003eATP10A\u003c/em\u003e p.Ala881Val variant in participant R170 who presented with confusional migraine following minor head injury had been previously reported [39], and now a second rare, likely damaging \u003cem\u003eATP10A\u003c/em\u003e variant (p.Glu81Gly) in a case presenting with migraine without aura and memory problems after several concussions was identified.\u003c/p\u003e\n\u003cp\u003ePathogenic LoF variants in \u003cem\u003eATP7B\u003c/em\u003e cause the autosomal recessive Wilson disease due to impaired copper metabolism in which the basal ganglia and liver undergo changes that express themselves in neurologic manifestations, and signs of cirrhosis, respectively [74]. Neurological manifestations include changes in personality and behaviour, similar to what may occur following TBI. We previously reported the heterozygous \u003cem\u003eATP7B\u003c/em\u003e p.Leu795Phe variant in patient R211 that presented with severe migraine and ataxia following head injury [39]. Included with the current study, we have identified six participants out of 93 who have had concussion with a heterozygous novel or rare \u003cem\u003eATP7B\u003c/em\u003e missense variants previously described as pathogenic, or of uncertain significance, for Wilson disease, while the frequency of heterozygous pathogenic \u003cem\u003eATP7B\u003c/em\u003e variants carriers in the population is estimated as only ~1 per 90 [75]. It is possible that heterozygous mutations in this gene may contribute to concussion with head injury acting as trigger on the risk allele [39], reflecting the role of metal ions in neurophysiology, and the dysregulation that may occur in TBI [76].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePotassium channel genes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePotassium channels are a diverse ion channel group with five types defined by their activators: voltage-gated, calcium-activated, inwardly rectifying, ATP-sensitive and sodium-activated [77]. Rare and likely deleterious variants were identified in potassium channel genes \u003cem\u003eKCNJ10\u003c/em\u003e and \u003cem\u003eKNCT2\u003c/em\u003e. \u003cem\u003eKCNJ10\u003c/em\u003e, a member of the inward rectifier-type potassium channel family (Kir4.1), has a role in maintaining the ionic environment in the extracellular space, acting as a modulator of neuronal activity and the glutamatergic system. Kir4.1 dysfunction has been linked to neurological conditions including depression and epilepsy [78], and it is downregulated in murine models of neurodegeneration, with resulting increased neuronal hyperexcitability a\u0026nbsp;possible driver of neuronal loss\u0026nbsp;[79]. We previously reported R117 carrying the p.Arg18Trp variant [39], who\u0026nbsp;presented with recurrent episodes of pallor and vomiting following minor head injury, and sensitivity to loud noises and light for three weeks, while CN32 with a \u003cem\u003eKCNJ10\u003c/em\u003e p.Lys354Arg variant, had sustained multiple concussions, but reported no ongoing or long-term symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eKCNT2\u003c/em\u003e encodes a sodium-activated potassium channel (also known as SLICK) which is widely expressed across the CNS, modulating membrane hyperpolarization and adapting neuronal firing patterns [80]. Pathogenic \u003cem\u003eKCNT2\u003c/em\u003e variants have been identified in development and epileptic encephalopathies (DEE) [81,80], although no functional or clinical data is available for the p.Lys929Glu and p.Ile542Leu variants identified here.\u003c/p\u003e\n\u003cp\u003eInterestingly, another exploratory exome-based study of 50 concussion patients found multiple rare variants with predicted high impact in \u003cem\u003eKCNN3\u003c/em\u003e, which encodes a calcium-activated potassium channel (K\u003csub\u003eCa\u003c/sub\u003e2.3) that regulates neuronal excitability by dampening calcium mediated neuronal firing frequency [82]. It is possible that the functional effects of the channel variants identified in these studies are not significantly different from those of wild type channels, except perhaps in the context of significant ionic dysregulation as occurs in concussion. Further functional assays would be required to test this hypothesis. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNeurotransmission-related genes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs research has shown that following concussion there is a release of neurotransmitters such as glutamate [23], and that damaged neurons demonstrate reduced or inhibited neuronal signaling in some neuron subtypes [83], we hypothesized that genes in pathways regulating neurotransmission may also harbor genetic variants that play a role in concussion.\u003c/p\u003e\n\u003cp\u003eRare variants were identified in various neurotransmission-related genes including: \u003cem\u003eCHAT\u003c/em\u003e (p.Arg323His, p.Leu458Phe, p.Arg561Gln), \u003cem\u003eDAGLB\u003c/em\u003e (p.Ile596Thr), \u003cem\u003eKIF17\u003c/em\u003e (p.Glu807Ala, p.Arg111Gly, p.Glu65Lys), \u003cem\u003eNRG1\u003c/em\u003e (p.Thr416Ser), \u003cem\u003eSNCAIP\u003c/em\u003e (p.Val213Met, p.Arg621Cys, p.Glu709Gln, p.Arg608His), \u003cem\u003eSV2C\u003c/em\u003e (p.Val321Glu, p.Asp456Asn), \u003cem\u003eSYT9\u003c/em\u003e (p.Arg85Gln, p.Leu353Val) and \u003cem\u003eUNC13B\u003c/em\u003e (p.Arg687Gln, p.Ser760Ile, p.Asn1035Lys). Further information on these genes is detailed in Supplementary Information 6. Several of these genes have been linked to cognitive function and particularly have been associated with Alzheimer’s and/or Parkinson’s disease. For example, ten participants in the concussion cohort had variants in the \u003cem\u003eSNCAIP\u003c/em\u003e gene (five with p.Glu709Gln and three with p.Arg806His). \u003cem\u003eSNCAIP\u003c/em\u003e encodes synuclein alpha-interacting protein or synphilin-1. It is enriched at synaptic terminals, has a role in regulating energy homeostasis and cellular ATP levels, and is associated with alpha-synuclein and inclusion bodies in Parkinson’s disease [84,85]. The relationship between Parkinson’s disease and head injury is not clearly understood, although some studies have shown increased risk of Parkinson’s disease in those who have suffered mild to moderate head injury. For example, a significant increased risk for Parkinson's disease diagnosis later in life was found in a cohort of 47,483 individuals with a concussion (Odds ratio = 1.57; 95% CI [1.41,1.75]; p \u0026lt;0.001) [86]. A similarly large study of veterans also identified 56% increased risk of Parkinson’s disease in military veterans who had suffered mild traumatic brain injury [87]. These data add to the body of evidence suggesting that there may be some overlap of the genetic risk factors for concussion and Parkinson’s disease.\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eWe acknowledge the relatively small size of the cohort (n=93), which means we have limited analysis to an overall neuronal vulnerability hypothesis rather than grouping concussion outcomes and post-concussion symptoms, so some of our findings may be related to specific outcomes rather than initial vulnerability to concussion. We also suggest that generalizable conclusions will need to be explored in larger TBI/concussion cohorts, with clear groups based on concussion outcomes optimal for analysis. The limited sample size also meant we could not use a genome-wide approach for analysis or burden testing and acknowledge that targeting gene sets may miss important gene variants or identify rare variants that are not necessarily linked to our hypothesis. We have attempted to limit the latter through filtering to include only genes with predicted deleterious variants in more than one participant and propose that these genes are prioritized for further investigation to validate these findings. Not all individuals in the cohort had coding variants in the genes that were targeted for analysis, and our study does not preclude the roll of other genes, non-coding or common variants, and non-genetic mechanisms in concussion.\u0026nbsp;\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eIn conclusion, we have identified potentially deleterious coding variants in a series of neuronal ion channels and other synaptic genes in study participants who had sustained concussion/s. Many of these genes have been previously linked to disorders that show overlapping symptomology with post-concussion symptoms. We propose that while many of the identified heterozygote variants may be subclinical under normal conditions, dysfunction may be revealed after head trauma which disrupts ion homeostasis and requires recovery of ionic and excitatory/inhibitory balance leading to the shared phenotypes post-concussion. Genes encoding ion channel proteins, especially those involved in calcium and sodium ion transport, are of particular interest. We also found many candidate variants in genes involved in neurotransmission, and that have been associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. \u0026nbsp;The most recent consensus statement of concussion in sport notes that while currently genetic testing may be a valuable research tool in the study of concussion, it is not yet suitable for routine use in clinical practice [3]. Accordingly, our results provide important genetic information for further investigation to aid in developing useful markers for understanding concussion risk, predicting outcomes and prognosis, and in identifying potential targets for treatment strategies.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants who took part in this research and the Gallipoli Medical Research Foundation. We acknowledge investigators involved in the Gallipoli Medical Research Foundation project conception, recruitment and sample acquisition: PTSD Initiative Members of the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia - Sarah McLeay, Wendy Harvey, Madeline Romaniuk, Darrell Crawford, David Colquhoun, Ross McD Young, Miriam Dwyer, John Gibson, Robyn O\u0026apos;Sullivan, Graham Cooksley, Christopher Strakosch, Rachel Thomson, Joanne Voisey, and Bruce Lawford.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.R.G., A.G., R.A.L., A.M.J.M.M., and D.R.N. conceptualized the study and acquired funding. Participant recruitment and sample collection was facilitated by L.R.G., R.A.S., O.D., and F.A.N.. N.M. and O.D. conducted the exome sequencing. H.G.S conducted additional variant confirmation and genotyping. Data analyses were carried out by N.M., H.G.S., B.H.M., O.D., and R.A.L.. B.H.M. wrote the first draft of the manuscript. H.G.S. and N.M. contributed to further writing, and all co-authors reviewed and provided advice on the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was funded by a U.S. DOD Defense Health Program Congressionally Directed Medical Research Programs Traumatic Brain Injury and Psychological Health Research Program Investigator-Initiated Research Award FY18 (W81XWH-19-1-0098; PR180286) and an Australian National Health and Medical Research Council grant (NHMRC-APP1122387). Infrastructure used in the project was purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia - Queensland Node project. O.D. was a recipient of a QUT Faculty of Health Postgraduate Scholarship.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting the findings of this study are available within the paper and supplementary tables. Full participant sequencing data is not openly available due to ethics stipulations and reasons of privacy, however, specific information about genetic variants or genes in participants are available upon reasonable request to the corresponding author. Data are located in controlled access data storage at Queensland University of Technology. The novel sequence variant identified in this paper has been submitted to dbSNP for inclusion in the next available build (submission ID number 2137544578). When the build is completed by dbSNP, data will be available at: https://www.ncbi.nlm.nih.gov/SNP/snp_viewTable.cgi?handle=GENOMICSRESEARCHCENT\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.R.G. reports recent consultancy support from Teva, participates on the Aust Novartis migraine Advisory Board, and has received research support from VariantBio. She also serves as Chair for the Board of Censors, Diagnostic Genomics, Human Genetics Society Australasia. The other authors declare no conflicts of interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Approval was granted by the Human Research Ethics Committee (HREC) of Queensland University of Technology (QUT), (Project approval number 1400000748), with informed consent was obtained from all participants. All experiments were performed according to their guidelines and regulation of QUT HREC.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRao V, Syeda A, Roy D, Peters ME, Vaishnavi S (2017) Neuropsychiatric aspects of concussion: acute and chronic sequelae. 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Neurology 90(20):e1771\u0026ndash;e1779. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1212/WNL.0000000000005522\u003c/span\u003e\u003cspan address=\"https://doi:10.1212/WNL.0000000000005522\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Queensland University of Technology","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Concussion, genetics, ion channels, neurotransmitters, rare variants, traumatic brain injury","lastPublishedDoi":"10.21203/rs.3.rs-9528680/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9528680/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSome individuals are more susceptible to incurring concussion or mild traumatic brain injury (mTBI) and the range, severity, and persistence of neurological symptoms may also vary greatly, with genetic variation likely to play a role. Symptomatic overlap of post-concussion syndrome with neurological conditions such as familial hemiplegic migraine (FHM) caused by rare pathogenic variants in ion channel and synapse protein genes, and high sensitivity to head trauma for some patients, suggests a role for similar genetic variants in mTBI. In this study we investigated rare protein-altering variants in the known FHM genes, other ion channel or transporters, and genes involved in neurotransmission via whole exome sequencing and analysis of 93 unrelated individuals who had sustained a single or multiple concussions. Some 62 different rare missense variants were identified across 24 genes in 59 participants (63%), with 26 participants harbouring two or more variants. The prevalence of specific likely damaging rare variants in the 16 ion channel-related genes that were identified was ~\u0026thinsp;5-fold greater than that observed from gnomAD population controls (Odds Ratio\u0026thinsp;=\u0026thinsp;5.44, CI: 4.13, 7.18, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Voltage-gated calcium and sodium channel genes including \u003cem\u003eSCN9A\u003c/em\u003e, and specific neurotransmitter-related genes such as \u003cem\u003eSNCAIP\u003c/em\u003e, harboured numerous potentially deleterious variants. We suggest such genetic variants may predispose some individuals to be vulnerable to concussion or more severe post-concussion symptoms, precipitated by head trauma. Our results provide important genetic information for further investigation to aid in developing useful biomarkers for understanding concussion risk and prognosis.\u003c/p\u003e","manuscriptTitle":"Investigating vulnerability to concussion through rare ion channel and neurotransmitter genetic variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 07:58:20","doi":"10.21203/rs.3.rs-9528680/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b053859e-2004-4c04-94ef-d4ee1bd2e7d3","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67015800,"name":"Molecular Genetics"},{"id":67015801,"name":"Cellular \u0026 Molecular Neuroscience"},{"id":67015802,"name":"Neurobiology of Disease"}],"tags":[],"updatedAt":"2026-04-29T07:58:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 07:58:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9528680","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9528680","identity":"rs-9528680","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}