ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1940C>A (p.Ala647Asp) (rs185638763)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058465 SCV000089985 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:20129283).
Invitae RCV000465221 SCV000545011 uncertain significance Brugada syndrome 2016-06-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 647 of the SCN5A protein (p.Ala647Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual referred for Brugada testing (PMID: 20129283). However, one pathogenic allele (p.Pro1332Leu) was identified in the SCN5A gene, which suggests that this c.1940C>A substitution in SCN5A was not the primary cause of disease in this individual. ClinVar contains an entry for this variant (Variation ID: 67701). 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. One experimental study using cultured cells have shown that this missense variant reduced the sodium current density of SCN5A when co-expressed with wildtype SCN5A but had no effect when expressed by itself (PMID: 24573164). The relevance of this finding is uncertain. In summary, this variant is a rare missense change that has an impact on protein function but has been reported to co-occur with a known pathogenic variant in an affected individual. However, the available evidence is currently insufficient to determine its role in disease. For these reasons, it has been classified as a Variant of Uncertain Significance.

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