Submissions for variant NM_000335.5(SCN5A):c.4780G>A (p.Asp1594Asn)

dbSNP: rs137854607

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183084	SCV000235494	likely pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	Functional studies of D1595N using a whole-cell patch clamp technique identified a combination of biophysical abnormalities expected to slow myocardial conduction velocity (Wang et al., 2002); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 9385; ClinVar); This variant is associated with the following publications: (PMID: 11804990)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183084	SCV000545100	pathogenic	not provided	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1595 of the SCN5A protein (p.Asp1595Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant SCN5A-related conditions (PMID: 11804990; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9385). 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: 11804990). 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: 15671429, 18048769). 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.
Baylor Genetics	RCV001329632	SCV001521125	pathogenic	Atrial fibrillation, familial, 10	2020-01-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
PreventionGenetics, part of Exact Sciences	RCV004528098	SCV004108243	likely pathogenic	SCN5A-related disorder	2023-06-05	criteria provided, single submitter	clinical testing	The SCN5A c.4783G>A variant is predicted to result in the amino acid substitution p.Asp1595Asn. This variant was reported in an individual with atrioventricular conduction block. Furthermore the proband's father and sister had evidence of right bundle-branch block, left axis deviation, and a normal PR interval. Functional studies also support this variant impacts SCN5A function (Wang et al. 2002. PubMed ID: 11804990). A different missense variant impacting the same amino acid residue (p.Asp1595His) has been reported in an individual with dilated cardiomyopathy. Functional studies also support the deleterious nature of the p.Asp1595His variant (Olson et al. 2005. PubMed ID: 15671429; Nguyen et al. 2007. PubMed ID: 18048769). The p.Asp1595Asn variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
OMIM	RCV000009983	SCV000030204	pathogenic	Progressive familial heart block, type 1A	2002-01-22	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058705	SCV000090225	not provided	Atrioventricular block		no assertion provided	literature only	This variant has been reported as associated with Atrioventricular conduction block in the following publications (PMID:11804990). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.