rs199473631

Description

This sequence change replaces valine with methionine at codon 1763 of the SCN5A protein (p.Val1763Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 15485686, 23998552, 30847666). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 67974). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects SCN5A function (PMID: 15485686, 23998552). For these reasons, this variant has been classified as Pathogenic.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15485686;PMID:15840476;PMID:16379539;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PS2, PM2

The V1763M pathogenic variant in the SCN5A gene has been reported as a de novo variant in a newborn with congenital LQTS presenting with prenatal bradycardia and postnatal 2:1 atrioventricular block and torsade de pointes ventricular tachycardia (Chang et al., 2004). Similarly, V1763M has been identified as an apparently de novo variant in two unrelated probands with infantile LQTS referred for testing at GeneDx. V1763M was also reported in a 10-year-old child presenting with bradycardia during a viral infection who was subsequently diagnosed with cardiac sinus node dysfunction and found to be compound heterozygous for the V1763M and the D1792N variants in the SCN5A gene (Selly et al., 2012). V1763M has been reported in the published literature in an individual referred for LQTS genetic testing (Tester et al., 2005; Kapplinger et al., 2009), and has also been observed in multiple individuals referred for LQTS testing at GeneDx. The V1763M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).Although the V1763M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs in the S6 transmembrane domain of repeat IV at a position that is conserved across species. Multiple missense variants in nearby residues (I1758V, L1761F, L1761H, M1766V, M1766L, Y1767C, I1768V) and in the same residue (V1763L) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, electrophysiological studies demonstrated the V1763M variant causes persistent inwardcurrent due to altered inactivation kinetics (Chang et al., 2004; Ma et al., 2013).