ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3285G>A (p.Trp1095Ter) (rs759924541)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476938 SCV000545064 pathogenic Brugada syndrome 2016-04-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1095 (p.Trp1095*) of the SCN5A gene. It is expected to result in an absent or disrupted protein product. Truncating variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). A different variant (c.3284G>A) giving rise to the same protein effect observed here (p.Trp1095*) has been reported in a family affected with Brugada syndrome and epilepsy (PMID: 23538271). Also, the same same amino acidic change has been reported in an individual affected with Brugada syndrome but the nucleotide position involved has not been specified (PMID: 19561025). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000476938 SCV000966950 likely pathogenic Brugada syndrome 2018-05-04 criteria provided, single submitter clinical testing The p.Trp1095X variant in SCN5A has been reported in 1 individual with Brugada s yndrome (Yamagata 2017), and was absent from large population studies. The same amino acid change resulting from a different variant (c.3284 G>A) has been repor ted in another proband with Brugada syndrome and segregated with disease in 2 af fected relatives (Parisi 2013). The p.Trp1095X variant has also been reported in ClinVar (Variation ID 406434). This nonsense variant leads to a premature termi nation codon at position 1095, which is predicted to lead to a truncated or abse nt protein. Heterozygous loss of function of the SCN5A gene is an established di sease mechanism in Brugada syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp1095X variant i s likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2.

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