ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.883G>A (p.Glu295Lys) (rs762283891)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522530 SCV000620088 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing The E295K variant in the SCN5A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E295K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E295K variant 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. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E295K as a variant of uncertain significance
Invitae RCV000812828 SCV000953154 uncertain significance Brugada syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 295 of the SCN5A protein (p.Glu295Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs762283891, ExAC 0.002%). This variant has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 451392). 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 tolerated, 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.

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