ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.2428G>T (p.Gly810Trp) (rs145712124)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559316 SCV000637005 uncertain significance Brugada syndrome 2017-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 810 of the SCN10A protein (p.Gly810Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is present in population databases (rs145712124, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with atrial fibrillation (PMID: 25053638). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000786212 SCV000924934 uncertain significance not provided 2018-01-24 no assertion criteria provided provider interpretation p.Gly810Trp (G810W; c.2428G>T) in exon 15 of the SCN10A gene (NM_006514.3) Chromosome location 3:38770245 C / A Found in a 12-year-old male with a history of 2 unexplained syncopal episodes and a run of monomorphic VT on Holter monitor. Based on the information reviewed below, including a lack of case data, and prevalence in the broader population, we classify this as a VUS, Probably Benign. This variant is most common among individuals with Latino ancestry like our patient, and it may therefore be a benign ethnicity-specific variant. This variant has previously been reported in a European-American male individual diagnosed at age 51 with paroxysmal atrial fibrillation (PMID: 25053638). There is no published segregation data. This is a conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a nonpolar Tryptophan that has a much larger side chain. Glycine at this location is highly conserved across ~100 vertebrate species for which we have data, although it is a Serine in two mammalian species and an Arginine in another. The adjacent residues are not highly conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 75 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 17 Latino individuals (for the highest allele frequency: 0.05%), 56 non-Finnish Europeans (MAF 0.04%), and 2 individuals with African ancestry. (There are also 2 individuals with p.Gly810Arg.) Invitae’s report notes that it has an allele count higher than 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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