Submissions for variant NM_000335.5(SCN5A):c.4780G>C (p.Asp1594His)

dbSNP: rs137854607

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258074	SCV001434907	likely pathogenic	Brugada syndrome 1; Long QT syndrome 3	2019-12-31	criteria provided, single submitter	clinical testing	This c.4783G>C (p.Asp1595His) variant in SCN5A gene results in an amino acid change at residue 1595 from an aspartic acid to a histidine. This variant has been reported to cosegregate with dilated cardiomyopathy in a family (PMID: 15671429). It is absent from the general population database gnomAD. A different variant at the same codon c.4783G>A (p.Asp1595Asn) has been classified as pathogenic/likely pathogenic (ClinVar accession: VCV000009385.1). In vitro functional studies at amino acid position 1595 indicate that both p.Asp1595His (PMID: 18048769) and p.Asp1595Asn (PMID: 11804990) impair sodium channel function. Multiple lines of in silico algorithms predict the c.4783G>C (p.Asp1595His) variant to be deleterious. Based on the currently available evidence, we consider the variant c.4783G>C (p.Asp1595His) of SCN5A to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003156212	SCV001582275	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1595 of the SCN5A protein (p.Asp1595His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 15671429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9406). 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: 18048769). This variant disrupts the p.Asp1595 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11804990; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003156212	SCV003845469	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on sodium channel function (Nguyen et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); 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: 22581653, 15671429, 18048769)
OMIM	RCV000010009	SCV000030230	pathogenic	Dilated cardiomyopathy 1E	2005-01-26	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058706	SCV000090226	not provided	Primary dilated cardiomyopathy		no assertion provided	literature only	This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:15671429;PMID:18048769). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.