Submissions for variant NM_000335.5(SCN5A):c.1425A>C (p.Arg475Ser)

gnomAD frequency: 0.00014  dbSNP: rs199473116

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058422	SCV000760255	uncertain significance	not provided	2024-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 475 of the SCN5A protein (p.Arg475Ser). This variant is present in population databases (rs199473116, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 67662). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842281	SCV001353881	uncertain significance	Cardiac arrhythmia	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 475 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two healthy, African American individuals in the literature (PMID: 20129283, 15851227). This variant has been identified in 9/280488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002390208	SCV002698664	uncertain significance	Cardiovascular phenotype	2023-12-27	criteria provided, single submitter	clinical testing	The p.R475S variant (also known as c.1425A>C), located in coding exon 10 of the SCN5A gene, results from an A to C substitution at nucleotide position 1425. The arginine at codon 475 is replaced by serine, an amino acid with dissimilar properties. This variant has been detected in a cohort of individuals with pacemakers (Celestino-Soper PB et al. PLoS One. 2016 Jan;11(1):e0147455); however, detail was limited. This variant has also been detected in ostensibly healthy cohorts (Ackerman MJ et al. Heart Rhythm, 2004 Nov;1:600-7; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This alteration has also been reported in a sudden death cohort and a pediatric dilated cardiomyopathy (DCM) cohort (Salfati EL et al. Genome Med, 2019 Dec;11:83; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483109	SCV002794056	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-09-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842281	SCV004823397	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 475 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two healthy, African American individuals in the literature (PMID: 20129283, 15851227). This variant has been identified in 9/280488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058422	SCV000089942	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).