ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3010_3022del (p.Cys1004fs) (rs1064792926)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482498 SCV000570122 likely pathogenic not provided 2016-04-28 criteria provided, single submitter clinical testing Although the c.3010_3022del13 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 Cystine 1004, changing it to a Proline, and creating a premature stop codon at position 137 of the new reading frame, denoted p.Cys1004ProfsX137. 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. Multiple other downstream frameshift variants in the SCN5A gene have been reported in HGMD in association with Brugada syndrome or other SCN5A-related disorders (Stenson et al., 2014). Furthermore, the c.3010_3022del13 variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.3010_3022del13 in the SCN5A gene is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype.
Invitae RCV000476373 SCV000545021 pathogenic Brugada syndrome 2016-11-04 criteria provided, single submitter clinical testing This sequence change deletes 13 nucleotides from exon 17 of the SCN5A mRNA (c.3010_3022delTGCATTGCCACCC), causing a frameshift at codon 1004. This creates a premature translational stop signal (p.Cys1004Profs*137) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.

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