ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2440C>T (p.Arg814Trp) (rs199473161)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183003 SCV000235408 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing The R814W pathogenic variant in the SCN5A gene has been reported as a de novo variant in one individual with dilated cardiomyopathy, atrial flutter, and non-sustained ventricular tachycardia (Olson et al., 2005). Golbus et al. (2014) identified R814W in a proband with familial DCM, arrhythmia, congestive heart failure, and history of heart transplant; the variant segregated with disease phenotype in multiple affected relatives. The R814W variant has been observed in several unrelated individuals referred for cardiogenetic testing at GeneDx. Furthermore, the R814W variant is not observed in large population cohorts (Lek et al., 2016).R814W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs in the voltagesensing transmembrane segment (S4) of domain II at a position that is conserved across species (Olson et al., 2005). Several functional studies demonstrated that R814W alters sodium channel properties (Nguyen et al., 2008; Beckermann et al., 2014; Moreau et al., 2015). Finally, a likely pathogenic missense variant at the same residue (R814Q) has previously been reported in association with arrhythmia (Frigo et al., 2017; Sommariva et al., 2013; Itoh et al., 2016; Yamagata et al., 2017), further supporting the functional importance of this residue.
Laboratory for Molecular Medicine, Partners HealthCare 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
Invitae RCV000457460 SCV000545073 pathogenic Brugada syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 814 of the SCN5A protein (p.Arg814Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature to occur de novo in an individual affected with dilated cardiomyopathy (PMID: 15671429). It has also been reported to segregate with disease in one family affected with cardiomyopathy (PMID: 25179549). ClinVar contains an entry for this variant (Variation ID: 67731). Experimental studies have shown that this missense change alters the SCN5A channel functional properties (PMID: 24815523, 18048769, 26733869). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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 Ventricular extrasystoles; Left ventricular noncompaction cardiomyopathy; Ventricular tachycardia 2019-11-22 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM4,PP3,PM2,PS2. This variant was detected in heterozygous state.
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 (, 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.

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