ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2582_2583del (p.Phe861fs) (rs794728914)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201886 SCV000256654 pathogenic Brugada syndrome 2015-04-14 criteria provided, single submitter research The SCN5A Phe861Trpfs*90 has been previously described in individuals with Brugada syndrome and/or family members undergoing genetic testing (Chockalingam et al, 2012; Kapplinger JD, et al., 2010; Meregalli PG, et al., 2009; Schulze-Bahr E, et al., 2003) and was absent from >1300 controls (Kapplinger JD, et al., 2010). The variant is absent from the 1000 genomes project (http://www.1000genomes.org/) and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified the SCN5A Phe861Trpfs*90 variant in a young boy who initially presented with recurrent syncope, and was found to have a type 1 Brugada pattern on ECG. Subsequent family screening revealed 2 other siblings and the mother to be clinically affected, and genetic testing found the variant to co-segregate with disease in this family. The Phe861Trpfs*90 variant is predicted to cause a frameshift at codon 861 and lead to a premature stop codon 90 amino acids downstream. In summary, based on the current literature, rarity in populations, our familial data and that loss-of-function mutations in the SCN5A gene are an established mechanism of disease, we classified the Phe861Trpfs*90 variant as "pathogenic".
GeneDx RCV000183155 SCV000235571 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing The c.2582_2583delTT pathogenic variant in the SCN5A gene has been previously reported in multiple individuals in association with Brugada syndrome and progressive cardiac conduction disease (Schulze-Bahr et al., 2003; Gaborit et al., 2009; Meregalli et al., 2009; Zumhagen et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Hofman et al., 2013). It has also been shown to segregate with disease in at least one other affected relative in one family (Schulze-Bahr et al., 2003). This variant causes a shift in reading frame starting at codon phenylalanine 861, changing it to a tryptophan, and creating a premature stop codon at position 90 of the new reading frame, denoted p.Phe861TrpfsX90. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.2582_2583delTT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

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