ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1603C>T (p.Arg535Ter) (rs1417036453)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000610147 SCV000731482 pathogenic Brugada syndrome 2018-07-06 criteria provided, single submitter clinical testing The p.Arg535X variant in SCN5A has been reported in at least 9 individuals (8 w ith Brugada syndrome and 1 referred for Long QT syndrome testing), and segregate d with disease in 4 affected relatives from 1 family (Smits 2002, Keller 2005, P robst 2009, Meregalli 2009, Kapplinger 2010, Lieve 2013). This variant has been reported in ClinVar (variation ID: 517279) and has been identified in 1/17212 Ea st Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org/). This nonsense variant leads to a premature termination codo n at position 535, which leads to a truncated protein that lacks WT function as shown by in vitro studies (Keller 2005). Heterozygous loss of function variants in the SCN5A gene have been reported in individuals with Brugada syndrome (Kappl inger 2010), DCM (Olson 2005), ventricular fibrillation (Chen 1998), as well as AV block and cardiac conduction defects (Baruteau 2012). In summary, this varian t meets criteria to be classified as pathogenic for Brugada syndrome in an autos omal dominant manner based upon segregation studies, presence in affected indivi duals and, functional evidence. ACMG/AMP criteria applied: PVS1, PM2, PS4_Modera te, PP1 (Richards 2015).
Ambry Genetics RCV000617180 SCV000738079 pathogenic Cardiovascular phenotype 2018-12-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes);Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Invitae RCV000610147 SCV000816703 pathogenic Brugada syndrome 2019-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg535*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with SCN5A-related arrhythmia (PMID: 12106943, 23631430, 20129283). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845417 SCV000987486 pathogenic Familial dilated cardiomyopathy criteria provided, single submitter clinical testing
GeneDx RCV001008643 SCV001168417 pathogenic not provided 2019-03-18 criteria provided, single submitter clinical testing The R535X pathogenic variant in the SCN5A gene has been reported in association with Brugada syndrome (Smits et al., 2002; Probst et al., 2009; Kapplinger et al., 2010). Additionally, this variant segregated with Brugada syndrome in multiple members of one family (Probst et al., 2009). The R535X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, functional studies demonstrate that this variant leads to a loss of channel function (Keller et al., 2005). Other nonsense variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014). Furthermore, the R535X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, R535X in the SCN5A gene is interpreted as a pathogenic variant.

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