Submissions for variant NM_000335.5(SCN5A):c.2701G>A (p.Glu901Lys)

dbSNP: rs199473174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001762168	SCV001374175	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 901 of the SCN5A protein (p.Glu901Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Brugada syndrome (PMID: 20129283, 22984773, 30193851; Invitae). ClinVar contains an entry for this variant (Variation ID: 67752). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946, 35305865). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001762168	SCV001989330	uncertain significance	not provided	2019-06-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24136861, 20129283, 25904541, 22984773, 30193851, 30662450, 32533946, 33131149)
3billion	RCV005252727	SCV005904875	pathogenic	Brugada syndrome 1	2023-10-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32533946). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.74 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000067752 /PMID: 20129283). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV005403751	SCV006066219	pathogenic	Cardiovascular phenotype	2025-01-30	criteria provided, single submitter	clinical testing	PM1_strong, PS3_mod, PS4_mod, PM2, PP2, PP3
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058521	SCV000090041	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.