ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5458_5459del (p.Leu1820fs) (rs1553692660)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518855 SCV000620965 likely pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing Although the c.5461_5462delCT likely pathogenic variant in the SCN5A gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon leucine 1821, changing it to a valine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Leu1821ValfsX2. This likely pathogenic variant located in the C-terminus end of the protein is predicted to result in protein truncation, as the last 196 amino acids are lost and replaced with 1 incorrect amino acids. Other downstream nonsense and frameshift variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.5461_5462delCT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000812319 SCV000952630 pathogenic Brugada syndrome 2018-08-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN5A gene (p.Leu1821Valfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 196 amino acids of the SCN5A protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 452184). Several different truncations (p.Tyr1995*, p.Arg1958*, p.Glu1867*) that lie downstream of this variant have been determined to be pathogenic (PMID: 27532257, 19862833, Invitae). This suggests that deletion of this region of the SCN5A protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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