ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3570G>A (p.Trp1190Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000818046 SCV000958640 pathogenic Brugada syndrome 2018-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1191*) 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 a family affected with Brugada syndrome (PMID: 17141278). Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). Experimental studies have shown that this nonsense change is associated with loss of function of the cardiac sodium channel (PMID: 17141278). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000818046 SCV000967726 likely pathogenic Brugada syndrome 2018-12-20 criteria provided, single submitter clinical testing The p.Trp1191X variant in SCN5A has been reported in 1 Korean individual with Br ugada syndrome and segregated with disease in 1 affected family member (Shin 200 7). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1191, which is predicted to lead to a truncated or absent protein. In vitro functional studies support that this varia nt results in a loss of protein function (Shin 2007). Heterozygous loss of funct ion of the SCN5A gene is an established disease mechanism in Brugada syndrome. H owever, it should be noted that additional phenotypes related to SCN5A loss of f unction (including long QT syndrome, atrial fibrillation, and other arrhythmias) have been described (Remme 2013). In summary, although additional studies are r equired to fully establish its clinical significance, this variant meets criteri a to be classified as likely pathogenic for autosomal dominant Brugada syndrome. ACMG/AMP Criteria applied: PVS1, PM2.

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