ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.2441G>A (p.Arg814His) (rs139861061)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765746 SCV000897114 uncertain significance Episodic pain syndrome, familial, 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000485771 SCV000568360 uncertain significance not provided 2019-01-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN10A gene. The R814H variant has previously been reported in association with either atrial fibrillation or arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (Savio-Galimberti et al., 2014; Jabbari et al., 2015; Te Riele et al., 2016). However, as described above, all reported individuals also harbored a second missense variant in the SCN10A gene, Y158D, confirmed to be on the same allele (in cis) in at least three unrelated patients. The R814H variant has not been published in isolation to our knowledge. However, this variant has been identified without a co-occurring Y158D variant in one proband referred for cardiology genetic testing a GeneDx, though this individual did harbor additional disease-related variants. This variant is observed in 63/125984 (0.05%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The R814H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Functional studies demonstrated that R814H generated a peak sodium current approximately four times larger than wild type (Savio-Galimberti et al., 2014). Nonetheless, additional studies are needed to validate the functional effect of this variant in vivo.
Invitae RCV000535345 SCV000637006 uncertain significance Brugada syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 814 of the SCN10A protein (p.Arg814His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs139861061, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with atrial fibrillation and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 25053638, 25085921, 26733327). All reported individuals also carried another change (c.472T>G, p.Tyr158Asp) that was shown to be in cis in at least three individuals (PMID: 25053638, 26733327). ClinVar contains an entry for this variant (Variation ID: 420025). Experimental studies in vitro have shown that this missense change generates a peak current that is 4 times larger than that of wild type (PMID: 25053638). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000485771 SCV000924933 uncertain significance not provided 2018-01-24 no assertion criteria provided provider interpretation p.Arg814His (c.2441G>A) in exon 15 of the SCN10A gene (NM_006514.3) Chromosome position: 3:38770232 C / T Found in a male patient with early-onset lone atrial fibrillation. The SCN10A gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with Brugada syndrome (BrS) (PMID: 24998131). Based on the information reviewed below, including this variant’s prevalence in population databases, and how poorly conserved this residue is across evolution, we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has been reported in 4 probands: 3 affected with early-onset atrial fibrillation (2 from Savio-Galimberti et al., 2014, PMID: 25053638; and 1 from Jabbari et al., 2015, PMID: 25691686) and 1 with arrhythmogenic right ventricular dysplasia/cardiomyopathy (Te Riele et al., 2016, PMID: 26733327). All reported individuals also carried another change (c.472T>G, p.Tyr158Asp) that was shown to be on the same allele (in cis) in at least three of these cases (Savio-Galimberti et al., 2014, PMID: 25053638; Te Riele et al., 2016, PMID 26733327). Savio-Galimberti et al. (2014) report that in their two families, first degree relatives with the variant(s) did not show atrial fibrillation, possibly due to reduced penetrance. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is very poorly conserved across ~100 vertebrate species for which we have data. There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10). Experimental studies in vitro have shown that this missense change generates a peak current that is 4 times larger than that of wild type (Savio-Galimberti et al., 2014; PMID: 25053638). This variant was reported in 85 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. (MAF = 0.03%.) Specifically, the variant was observed in 63 individuals with non-Finnish European ancestry (for the highest allele frequency: 0.05%), and 7 individuals with Latino ancestry, 5 African ancestry, 4 Finnish ancestry, 3 South Asian ancestry, and 3 “Other”. Our patient’s ancestry is Latino. This variant is present at a higher frequency than would be expected for a pathogenic variant. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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