ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1576C>T (p.Arg526Cys) (rs575883763)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522268 SCV000618734 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing The R526C variant of uncertain significance in the SCN5A gene has not been published as pathogenic or been reported as benign to our knowledge. The R526C variant was observed in 4/7,126 (0.06%) alleles from individuals of Latino ancestry in the Exome Aggregation Consortium (Lek et al., 2016). R526C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R523C, S524Y, F530V) and in the same residue (R526H) have been reported in the Human Gene Mutation Database in association with multiple phenotypes (Stenson et al., 2014), however, the pathogenicity of these variants has not been definitively determined.
Invitae RCV000476821 SCV000545107 uncertain significance Brugada syndrome 2018-02-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 526 of the SCN5A protein (p.Arg526Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs575883763, ExAC 0.06%). This variant has not been reported in the literature in individuals with SCN5A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.

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