ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2466G>A (p.Trp822Ter) (rs1553700699)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000604844 SCV000713339 pathogenic Brugada syndrome 2017-12-13 criteria provided, single submitter clinical testing The p.Trp822X variant in SCN5A has been reported in a pair of male monozygotic t wins who died from sudden infant death syndrome (SIDS; Turillazzi 2008). This va riant was absent from large population studies. This same amino acid change (p.T rp822X) from a different cDNA change (c.2465G>A) has also been identified in one individual with Brugada syndrome and segregated with disease in one affected re lative (Keller 2005). In vitro functional studies provide some evidence that the p.Trp822X variant may impact protein function (Keller 2005, Turillazzi 2008). T his nonsense variant leads to a premature termination codon at position 822, whi ch is predicted to lead to a truncated or absent protein. Loss of function varia nts in SCN5A are typically associated with Brugada syndrome although overlapping presentations including other SCN5A related phenotypes (Long QT syndrome) have been described (Remme 2013). In summary, this variant meets criteria to be class ified as pathogenic for Brugada syndrome in an autosomal dominant manner based u pon impact to the protein, functional evidence, and absence from controls. ACMG/ AMP Criteria applied: PVS1, PM2, PP3_Supporting (Richards 2015).

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