ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.6014del (p.Pro2005fs)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
MGZ Medical Genetics Center RCV002288292 SCV002579744 uncertain significance Dilated cardiomyopathy 1E 2021-12-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003097764 SCV003525138 uncertain significance Brugada syndrome 2022-09-17 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the SCN5A gene (p.Pro2006Leufs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the SCN5A protein and extend the protein by 20 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with Brugada syndrome (PMID: 22247482). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV004804418 SCV005428192 uncertain significance Cardiac arrhythmia 2024-05-30 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 28 of the SCN5A gene, causing a frameshift in the last exon and addition of 31 new amino acids before introducing a stop codon. This results in a protein product that is 20 amino acids longer than the normal protein product. This variant (referred to as p.P2006fsX2037) has been reported in a compound heterozygous state with a pathogenic SCN5A variant (c.2102del, p.Pro701Argfs*10) in an individual affected with progressive familial heart block type 1 and Brugada syndrome (PMID: 22247482). Further functional experiments from the same study demonstrated that cells expressing these two compound heterozygous variants exhibited no sodium current (PMID: 22247482). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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