Submissions for variant NM_000335.5(SCN5A):c.2440C>T (p.Arg814Trp)

dbSNP: rs199473161

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183003	SCV000235408	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(R814W) alters sodium channel properties (Nguyen et al., 2008; Beckermann et al., 2014; Moreau et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 17442746, 18048769, 26733869, 26916278, 28363160, 27532257, 22581653, 31737537, 15671429, 24815523, 25179549)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220629	SCV000271264	likely pathogenic	Primary dilated cardiomyopathy	2015-10-31	criteria provided, single submitter	clinical testing	The p.Arg814Trp variant in SCN5A has been reported de novo in 1 individual with DCM and cardiac biopsy findings showing myocellular hypertrophy and interstitial fibrosis (paternity confirmed; Olson 2005). The variant was absent from large p opulation studies. In vitro functional studies showed that the p.Arg814Trp varia nt affected protein function (leading to altered sodium channel function; Nguyen 2008, Beckermann 2014). However, these types of assays may not accurately repre sent biological function. Computational prediction tools and conservation analys is also support pathogenicity. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Arg814Trp variant is lik ely pathogenic based on absence in the general population and de novo occurrence
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183003	SCV000545073	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 814 of the SCN5A protein (p.Arg814Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant SCN5A-related conditions (PMID: 15671429, 25179549). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67731). 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: 18048769, 24815523, 26733869). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587580	SCV000700026	pathogenic	Cardiovascular phenotype	2016-07-18	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.2440C>T (p.Arg814Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The SCN5A encoded protein has 24 TM segments organized into 4 domains (DI-DIV), each containing 6 TM. Arg814 is highly conserved across species and is located in the second voltage-dependent channel, four helix bundle domain and the second iron transport domain (segment 4 of DII; Moreau_Front Pharmacol_2015 and InterPro). Several related SCN5A variants classified as Pathogenic/Likely Pathogenic in ClinVar (p.R814W, p.R222Q, p.R219H, etc) neutralize arginine residues that are localized in the S4 segment of domain I and II (Olson etal., 2005; Laurentetal.,2012; Mannetal.,2012; Nairetal.,2012; Beckermannetal.,2014). When compared to the WT condition, the R814W mutant was shown to negatively shift the voltage dependence of activation, slow activation kinetics, and increase the sodium window current (Nguyen_2008). However, it is unclear if these functional alterations would cause DCM since a consensus on disease mechanism has not yet been established.This variant was absent in 113532 control chromosomes, but has been cited in at least 6 DCM patients in the literature, and show to co-segregate with the DCM phenotype in a large family. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic/Likely Pathogenic. Taken together, this variant is classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197653	SCV001368432	pathogenic	Sick sinus syndrome 1	2019-11-22	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262605	SCV001440537	likely pathogenic	Dilated cardiomyopathy 1E	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000587580	SCV002737596	pathogenic	Cardiovascular phenotype	2021-07-13	criteria provided, single submitter	clinical testing	The p.R814W pathogenic mutation (also known as c.2440C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2440. The arginine at codon 814 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the transmembrane DII-S4 region. This mutation was first reported as de novo in a sporadic dilated cardiomyopathy (DCM) case (Olson TM et al. JAMA, 2005 Jan;293:447-54). In addition, this variant was found to co-segregate with disease in two unrelated families with cardiomyopathy and arrhythmia findings in multiple relatives (Golbus JR et al. Circ Cardiovasc Genet, 2014 Dec;7:751-759; Zakrzewska-Koperska J et al. ESC Heart Fail, 2020 Oct;doi: 10.1002/ehf2.12993). This variant was also detected in a DCM genetic testing case and a suspected Brugada syndrome case; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Functional studies with this variant demonstrated hyperpolarized activation and slowed inactivation in sodium channels (Nguyen TP et al. Circ Res, 2008 Feb;102:364-71; Beckermann TM et al. Heart Rhythm, 2014 Aug;11:1446-53; Moreau A et al. Front Pharmacol, 2015 Dec;6:301). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000220629	SCV000090020	not provided	Primary dilated cardiomyopathy		no assertion provided	literature only	This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:15671429;PMID:18048769). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183003	SCV000280468	likely pathogenic	not provided	2012-04-27	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg814Trp (R814W) c.2440 C>T in exon 16 of the SCN5A gene (NM_198056.2) It has been estimated that SCN5A variants may explain 2-3% of cases of familial DCM (Hershberger et al 2008, 2013). In a kindred with DCM, sinus node dysfunction, supraventricular tachyarrhythmias, stroke and conduction delay Olsen et al (1996) found linkage to a locus containing SCN5A, with a LOD score of 6.09. McNair et al (2004) later found a specific SCN5A variant segregating with the disease in this family. Since then, several other cases have been reported (Olson et al 2005, McNair et al 2011, Ge et al 2008, Shi et al 2008, Bezzina et al 2003, Mann et al 2012), Laurent et al 2012, Nguyen et al 2 008, Watanabe et al 2011, Beckerman et al 2014). Given the strong case data (albeit mostly unpublished), the genotype-phenotype match in our patient, and the absence in unselected populations, we consider this variant likely disease and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least four unrelated cases of arrhythmia and/or cardiomyopathy (not including this patient's family). Note that most of these cases are unpublished. Olson et al 2005) reported the variant with disease: "identified in a 23-year-old woman (DC-96) with sporadic DCM (EF,30%), atrial flutter, and short runs of nonsustained ventricular tachycardia on 1 of 2 Holter monitor recordings. Cardiac biopsy revealed mild to moderate myocellular hypertrophy and mild interstitial fibrosis. Her parents and 7 siblings (aged from 19–36 years) had normal echocardiogram and electrocardiogram results. A heterozygous point mutation, C2440T, was identified in exon 16 resulting in an R814W substitution. The mutation arose de novo, because it was absent in the patient’s parents and siblings and biological paternity and maternity were verified (Figure 3)." The genetic testing lab shared that they have seen this variant in three other individuals with personal and family history cardiomyopathy and/or arrhythmias, including sudden cardiac death. There is one entry in ClinVar, from "Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust" who classify it as pathogenic (as of June 11th, 2015). It is unclear if this is based solely on literature or if they observed it in affected individuals within their lab. The variant is included in a few reviews, but without new data (ex. Norton et al 2012). Some in vitro work has been done on the variant: " R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased “window current.” This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies" (Nguyen et al 2008). Though it is important to note that there are common variants in ion channels that have an in vitro phenotype but do not cause severe genetic disease. The variant was not observed in the following published control samples: 500 individuals with normal ECGs and echocardiograms (Olson et al 2005). This variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of June 11th, 2015). Another variant at this codon, p.Arg814Gln is present in 2/56766 individuals in this dataset.