ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4813+3_4813+6dup

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000240648 SCV000299256 likely pathogenic Brugada syndrome 1 2016-02-18 criteria provided, single submitter clinical testing
Invitae RCV000638741 SCV000760287 likely pathogenic Brugada syndrome 2017-12-27 criteria provided, single submitter clinical testing This sequence change falls in intron 27 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Brugada syndrome in a multigenerational family (PMID: 15808832) and has been observed in an individual and a family with clinical variability, including Brugada syndrome and cardiac conduction disease (PMID: 15863661). ClinVar contains an entry for this variant (Variation ID: 254157). Experimental studies have shown that this intronic insertion results in aberrant splicing, which causes an in-frame deletion of 32 amino acids in exon 27 mRNA (PMID: 15808832, 15863661), giving rise to dysfunctional sodium channels (PMID: 15808832). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Centre of Medical Genetics, University of Antwerp RCV000638741 SCV001190333 pathogenic Brugada syndrome no assertion criteria provided research Variant was identified in several Brugada syndrome patients with variable severity of the phenotype. Additionally, in vitro functional studies indicate that the c.4813+3_4813+6dupGGGT variant disrupts normal sodium channel function (Rossenbacker 2005, PMCID: 15863661; Hong 2005, PMCID: 15808832).

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