ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4882C>T (p.Arg1628Ter) (rs199473284)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250943 SCV000320087 pathogenic Cardiovascular phenotype 2015-09-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
GeneDx RCV000442994 SCV000515730 pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing The R1629X variant in the SCN5A gene has been reported previously in one individual referred for Brugada syndrome testing,and was absent from 2,600 control alelles (Kapplinger J et al., 2010). While the 1000 Genomes Project reports R1629X wasobserved in 1/1006 alleles (0.1%) from individuals of European ancestry, this variant is absent from approximately 6500individuals in the NHLBI Exome Sequencing Project. R1629X is predicted to cause loss of normal protein function by proteintruncation. Specifically, the S4 transmembrane voltage sensor of DIV is predicted to be disrupted, and downstream sequencesincluding the S5 and S6 transmembrane domains and the C-terminal cytoplasmic domain are predicted to be absent. Furthermore,other nonsense variants in this region and in downstream regions of the SCN5A gene have been reported in the Human GeneMutation Database in association an SCN5A-related disorder (Stenson P et al., 2014). In summary, R1629X in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000698724 SCV000827405 pathogenic Brugada syndrome 2018-06-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN5A gene (p.Arg1629*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 388 amino acids of the SCN5A protein. This variant is present in population databases (rs199473284, ExAC 0.001%). This variant has been observed in an individual affected with Brugada syndrome (PMID: 25829473) and an individual referred for Brugada syndrome testing (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 264276). Experimental studies have shown that this nonsense change results in significantly decreased sodium channel current (PMID: 25829473). A different truncation (p.Glu1823Hisfs*10) that lies downstream of this variant has been determined to be pathogenic (PMID: 18361072, 17897635). This suggests that deletion of this region of the SCN5A protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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