ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3068G>A (p.Arg1023His) (rs199473592)

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Total submissions: 8
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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)
Invitae RCV000058546 SCV000291794 likely benign Brugada syndrome 2020-12-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV001282452 SCV000886080 uncertain significance none 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 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV001189665 SCV001356998 likely benign 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.
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.

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