Submissions for variant NM_000335.5(SCN5A):c.376A>G (p.Lys126Glu)

gnomAD frequency: 0.00001  dbSNP: rs185492581

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
All of Us Research Program, National Institutes of Health	RCV003996538	SCV004840881	uncertain significance	Cardiac arrhythmia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 126 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved N-terminus (a.a. 1-131) domain. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant affects sodium channel function in vitro (PMID: 23805106). This variant has been reported in two individuals affected with or suspected of having Brugada syndrome (PMID: 12051963, 20129283). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089487	SCV005834634	uncertain significance	not provided	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 126 of the SCN5A protein (p.Lys126Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 12051963, 20129283). ClinVar contains an entry for this variant (Variation ID: 67826). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 23805106). 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058601	SCV000090121	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12051963;PMID:20129283;PMID:20981092). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.