ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1428_1431del (p.Ser476fs) (rs794728906)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183145 SCV000235561 likely pathogenic not provided 2017-01-09 criteria provided, single submitter clinical testing The c.1428_1431delCAAG likely pathogenic variant in the SCN5A gene has been reported previously in one individual with a diagnosis of Brugada syndrome, and was not reported in 2,600 control alleles (Kapplinger J et al., 2010). In addition, the c.1428_1431delCAAG variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Serine 476, changing it to a Arginine, and creating a premature stop codon at position 30 of the new reading frame, denoted p.Ser476ArgfsX30. This 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 HGMD in association with arrhythmia (Stenson et al., 2014). While the c.1428_1431delCAAG variant has not been published, it is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype. Therefore, the presence of this variant indicates that this individual is likely at increased risk to develop arrhythmia. However, other genetic and environmental factors influence disease expression and severity, and some individuals with a likely pathogenic variant may never become symptomatic. Clinical correlation with this test result is recommended.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627161 SCV000748013 pathogenic Brugada syndrome 2017-07-27 criteria provided, single submitter clinical testing

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