ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2861_2862GA[2] (p.Glu955fs) (rs756159737)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482288 SCV000566378 likely pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing The c.2865_2866delGA likely pathogenic variant in the SCN5A gene has not been published aspathogenic or been reported as benign to our knowledge. This variant causes a shift in reading framestarting at codon glutamic acid 955, changing it to an aspartic acid, and creating a premature stopcodon at position 74 of the new reading frame, denoted p.Glu955AspfsX74. This likely pathogenicvariant is expected to result in either an abnormal, truncated protein product or loss of protein fromthis allele through nonsense-mediated mRNA decay. Other frameshift variants in the SCN5A genehave been reported in HGMD in association with arrhythmia and cardiomyopathy (Stenson et al.,2014). Furthermore, the c.2865_2866delGA variant is not observed in large population cohorts (Leket al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000532744 SCV000637109 pathogenic Brugada syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 17 of the SCN5A mRNA (c.2865_2866delGA), causing a frameshift at codon 955. This creates a premature translational stop signal (p.Glu955Aspfs*74) 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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