ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.535C>T (p.Arg179Ter) (rs1480085793)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825605 SCV000966949 likely pathogenic Brugada syndrome 2016-09-22 criteria provided, single submitter clinical testing The p.Arg179X variant in SCN5A has been previously reported in 2 individuals wit h Brugada syndrome and 1 individual with long QT syndrome (Kapplinger 2009, Kawa mura 2009, Le Scouarnec 2015). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 179, which is predicted to lead to a truncated or absent protein. Variants in SCN5A are ass ociated with DCM, Brugada syndrome, Long QT syndrome, and other conduction syste m abnormalities (Olson 2005, Zimmer 2008). In summary, although additional studi es are required to fully establish its clinical significance, the p.Arg179X vari ant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2.
Integrated Genetics/Laboratory Corporation of America RCV001194085 SCV001363349 pathogenic Brugada syndrome (shorter-than-normal QT interval) 2019-04-08 criteria provided, single submitter clinical testing Variant summary: SCN5A c.535C>T (p.Arg179X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 245822 control chromosomes. c.535C>T has been reported in the literature in individuals affected with Brugada Syndrome (Kawamura_SCN5A_2009, Kapplinger_2009, LeScouarnec_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no inward sodium currents as measured in whole-cell current recordings using HEK293 cells indicating that the mutation was entirely non-functional. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000825605 SCV001383471 pathogenic Brugada syndrome 2019-09-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg179*) 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 observed in individuals affected with Brugada syndrome or referred for longQT syndrome testing (PMID: 19075524, 25650408, 19716085). This variant has been reported to affect SCN5A protein function (PMID: 19075524). Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.

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