ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.3070G>A (p.Val1024Met) (rs201106879)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548565 SCV000637013 uncertain significance Brugada syndrome 2017-04-25 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1024 of the SCN10A protein (p.Val1024Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs201106879, ExAC 0.02%) but has not been reported in the literature in individuals with a SCN10A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786214 SCV000924937 uncertain significance not provided 2017-04-25 no assertion criteria provided provider interpretation Found in a 16 year-old male with lone atrial fibrillation and a family history of heart failure and arrhythmias. Testing was done at Invitae. p.Val1024Met (c.3070G>A) in exon 16 of the SCN10A gene (NM_006514.3) Chromosome position: 3:38768114 C / T The SCN10A gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant small fiber neuropathy (SFNP) (PMID: 23986244) and Brugada syndrome (BrS) (PMID: 24998131). Based on the information reviewed below, including that this is a conservative amino acid change at a residue that is poorly conserved across species, and where Methionine is accepted as the default in some species, 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 not previously been reported in the literature in association with disease. It had not been reported to ClinVar as of 4/25/2017. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is poorly conserved across ~80 vertebrate species for which we have data. In fact, Methionine is the default amino acid in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". These predictions have not been confirmed by published functional studies. There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10). This variant was reported in 4 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 individuals with African ancestry (for the highest allele frequency: 0.013%), and 2 individuals with Latino ancestry. Our patient’s ancestry is Latino. 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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