Submissions for variant NM_000335.5(SCN5A):c.6031C>T (p.Arg2011Cys)

gnomAD frequency: 0.00002  dbSNP: rs199473640

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001705714	SCV000545060	uncertain significance	not provided	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2012 of the SCN5A protein (p.Arg2012Cys). This variant is present in population databases (rs199473640, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 25904541, 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 68027). 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. 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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000515713	SCV000611766	uncertain significance	Long QT syndrome 3	2017-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842404	SCV000904480	uncertain significance	Cardiac arrhythmia	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2012 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 19716085), as well as in a control individual (PMID: 19406494). This variant has been identified in 8/187482 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.
Fulgent Genetics, Fulgent Genetics	RCV002498347	SCV002781384	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	2021-07-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162461	SCV003903679	uncertain significance	Cardiovascular phenotype	2023-02-27	criteria provided, single submitter	clinical testing	The p.R2012C variant (also known as c.6034C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 6034. The arginine at codon 2012 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in long QT syndrome cohorts, a Brugada syndrome cohort, and an arrhythmia genetic testing cohort; however, clinical details were limited in these cases (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Kotta CM et al. Int J Cardiol, 2010 Nov;145:45-8; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Walsh R et al. Genet Med, 2021 Jan;23:47-58). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001842404	SCV004831380	uncertain significance	Cardiac arrhythmia	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2012 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 19716085), as well as in a control individual (PMID: 19406494). This variant has been identified in 8/187482 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237493	SCV005888341	uncertain significance	not specified	2025-01-06	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.6034C>T (p.Arg2012Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 187482 control chromosomes, predominantly at a frequency of 0.00016 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6034C>T has been reported in the literature in individuals affected with Brugada Syndrome, Long QT syndrome and unknown arrhythmia, without strong evidence for causality (Kapplinger_2010, Marschall_SCN5A_2019, vanLint_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 31737537, 30847666). ClinVar contains an entry for this variant (Variation ID: 68027). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058827	SCV000090347	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics, Academic Medical Center	RCV001705714	SCV001919061	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001705714	SCV001963548	uncertain significance	not provided		no assertion criteria provided	clinical testing