ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2503T>G (p.Ser835Ala)

gnomAD frequency: 0.00002  dbSNP: rs1421700935
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003226960 SCV000760231 uncertain significance not provided 2024-10-18 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 835 of the SCN5A protein (p.Ser835Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 34930020). ClinVar contains an entry for this variant (Variation ID: 532087). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 34930020). 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.
GeneDx RCV003226960 SCV003923971 uncertain significance not provided 2022-11-08 criteria provided, single submitter clinical testing Reported in an individual with atrial fibrillation (Glazer et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In vitro functional analysis demonstrated electrophysiological function similar to wild type (Glazer et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34930020)
All of Us Research Program, National Institutes of Health RCV004003855 SCV004842935 uncertain significance Cardiac arrhythmia 2024-09-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV004025522 SCV005031214 uncertain significance Cardiovascular phenotype 2023-11-21 criteria provided, single submitter clinical testing The p.S835A variant (also known as c.2503T>G), located in coding exon 15 of the SCN5A gene, results from a T to G substitution at nucleotide position 2503. The serine at codon 835 is replaced by alanine, an amino acid with similar properties. This variant has been detected in an individual with atrial fibrillation; in vitro analyses from the same group indicated this variant may not impact peak channel current compared to wild type; however, additional evidence is needed to confirm this finding (Glazer AM et al. Circulation, 2022 Mar;145:877-891). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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