Submissions for variant NM_000335.5(SCN5A):c.5474G>A (p.Arg1825His)

gnomAD frequency: 0.00016  dbSNP: rs137854610

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154827	SCV000204509	uncertain significance	not specified	2018-02-27	criteria provided, single submitter	clinical testing	The p.Arg1826His variant in SCN5A has been previously reported in 1 infant with SIDS, 2 individuals with LQTS, and 1 individual with infantile-onset of HCM (Ack erman 2001, Kapplinger 2009, LMM data). It has also been identified in 7/24022 A frican chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs137854610) and reported in ClinVar (Variation ID 9389). Functional studies have shown that the Arg1826His variant impacts protein funct ion (Ackerman 2001). However, this in vitro assay may not accurately represent b iological function. Additional computational prediction tools and conservation a nalysis suggest that this variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1826His variant is uncertain. ACMG/AMP Criteria applied : PP3; PS4_Supporting; PS3_Supporting.
GeneDx	RCV000766811	SCV000235534	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrate a damaging effect showing slower decay of sodium current and 2-3 fold increase in late sodium current (Ackerman et al., 2001); however, it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 23304551, 24055113, 23465283, 28316956, 18378609, 30079003, 31043699, 33083721, 32746448, 31657683, 27077130, 11710892, 19716085)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766811	SCV000637182	uncertain significance	not provided	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1826 of the SCN5A protein (p.Arg1826His). This variant is present in population databases (rs137854610, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 11710892, 19716085, 30079003, 31657683; internal data). ClinVar contains an entry for this variant (Variation ID: 9389). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11710892). 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.
Ambry Genetics	RCV000619902	SCV000737585	uncertain significance	Cardiovascular phenotype	2024-09-19	criteria provided, single submitter	clinical testing	The p.R1826H variant (also known as c.5477G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5477. The arginine at codon 1826 is replaced by histidine, an amino acid with highly similar properties. This variant was first described in a sudden infant death syndrome (SIDS) cohort; however, in the case involving p.R1826H, the authors indicated the cause of death was undetermined since asphyxiation could not be ruled out. In the same study, functional in vitro analyses suggested this variant may adversely affect the sodium ion channel, resulting in persistent and increased late sodium current related to gain of function effects (Ackerman MJ et al. JAMA. 2001;286(18):2264-9). A second in vitro functional assay did not observe an impact on sodium current at room temperature, but authors observed a decrease in thermal stability at higher temperatures and suggested that the alteration may affect channel function at physiological termperatures (Gardill BR et al. Sci Rep. 2018;8:4483). In a study of long QT syndrome clinical genetic testing, this alteration was reported in two patients; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This variant has been detected in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Can J Cardio. 2013;29(9):1104-9; Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Amendola LM et al. Genome Res. 2015;25(3):305-15; Jamuar SS et al. EBioMedicine. 2016;5:211-6). An alteration involving the same amino acid position (p.R1826C c.5476C>T) has been described in a patient with paroxysmal atrial fibrillation (Darbar D et al. Circulation. 2008;117(15):1927-35). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV001841236	SCV001344625	uncertain significance	Cardiac arrhythmia	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1826 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant may have impact on the channel function in vitro (PMID: 11710892). This variant has been reported in a case with sudden infant death syndrome (PMID: 11710892) and in an individual affected with long QT syndrome (PMID: 31657683). This variant has been identified in 13/280928 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	RCV002476953	SCV002796970	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	2022-05-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001841236	SCV004815702	uncertain significance	Cardiac arrhythmia	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1826 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant may have impact on the channel function in vitro (PMID: 11710892). This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 11710892), long QT syndrome (PMID: 31657683), and Ehlers-Danlos syndrome (PMID: 38534782). This variant has been reported not to be associated with a prolonged QTc interval in the Icelandic population (PMID: 37449562). This variant has been identified in 13/280928 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	RCV000154827	SCV005040373	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5477G>A (p.Arg1826His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.2e-05 in 1613756 control chromosomes, predominantly at a frequency of 0.00039 within the African or African-American subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5477G>A has been reported in the literature in individuals affected with Long QT Syndrome and in association with SIDS (Kapplinger_2009, Ackerman_2001) without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in vitro, however the biological impact of this study is unclear (Ackerman_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11710892, 19716085). ClinVar contains an entry for this variant (Variation ID: 9389). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
OMIM	RCV000009987	SCV000030208	pathogenic	Long QT syndrome 3	2001-11-14	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058786	SCV000090306	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:11710892;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148848	SCV000190591	uncertain significance	SUDDEN INFANT DEATH SYNDROME	2014-06-01	no assertion criteria provided	research