Submissions for variant NM_000335.5(SCN5A):c.3068G>A (p.Arg1023His)

gnomAD frequency: 0.00006  dbSNP: rs199473592

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757741	SCV000235431	likely benign	not provided	2019-05-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16344400, 24573164, 17512504, 25935074, 23168001, 29728395, 27560382, 30662450, 33131149)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757741	SCV000291794	likely benign	not provided	2025-01-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183023	SCV000540284	uncertain significance	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Brugada proband; also 1 paper reporting functional impact; However, frequency high for disorder; ClinVar: P by GeneDx
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757741	SCV000886080	uncertain significance	not provided	2020-05-28	criteria provided, single submitter	clinical testing	The SCN5A c.3068G>A; p.Arg1023His variant (rs199473592) is reported in the literature in an individual affected with Brugada syndrome (Frustaci 2005). This variant was also reported in an individual affected with long QT syndrome; however, this individual also carried a frameshift variant in a different gene that likely explained their phenotype (Fernandes 2015). The p.Arg1023His variant is found in the South Asian population with an overall allele frequency of 0.19% (57/30564 alleles) in the Genome Aggregation Database. The arginine at codon 1023 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Another amino acid substitution at this codon (p.Arg1023Cys) has been reported in individuals with Brugada syndrome or ventricular arrhythmia, but its clinical significance has not been conclusively demonstrated (Matsumura 2017, Watanabe 2013). Functional studies of the p.Arg1023His variant provide conflicting results. One study reported a lower peak current density and longer time of inactivation (Frustaci 2005), while a second study found normal peak current density in cells expressing p.Arg1023His alone and greater peak current density when expressed together with wildtype SCN5A (Hoshi 2014). Due to conflicting information, the clinical significance of the p.Arg1023His variant is uncertain at this time. References: Fernandes M et al. Long QT syndrome with mutations in three genes: A rare case. Rev Port Cardiol. 2015;34(5):359.e1-359.e3595. Frustaci A et al. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. 2005 Dec 13;112(24):3680-7. Hoshi M et al. Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circ Cardiovasc Genet. 2014 Apr;7(2):123-31. Matsumura H et al. H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters. J Biomed Sci. 2017;24(1):91. Watanabe H et al. SCN5A mutation associated with ventricular fibrillation, early repolarization, and concealed myocardial abnormalities. Int J Cardiol. 2013;165(2):e21-e23.
Mendelics	RCV000987212	SCV001136461	benign	Brugada syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842327	SCV001356998	likely benign	Cardiac arrhythmia	2018-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183023	SCV001363140	likely benign	not specified	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3068G>A (p.Arg1023His) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 275816 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant may be benign. c.3068G>A has been reported in the literature in at least one individual affected with Arrhythmia (Frustaci_2005). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity as measured by voltage gated sodium current density (Frustaci_2005, Hoshi_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one of whom have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002444521	SCV002753844	likely benign	Cardiovascular phenotype	2019-02-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486633	SCV004239663	likely benign	Cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058546	SCV000090066	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16344400). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.