Submissions for variant NM_000335.5(SCN5A):c.5809G>A (p.Glu1937Lys)

gnomAD frequency: 0.00003  dbSNP: rs199473329

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001562116	SCV000291825	uncertain significance	not provided	2025-01-26	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 1938 of the SCN5A protein (p.Glu1938Lys). This variant is present in population databases (rs199473329, gnomAD 0.006%). This missense change has been observed in individuals with Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 68012). 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 tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24573164). 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.
GeneDx	RCV001562116	SCV001784833	uncertain significance	not provided	2020-12-24	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 68012; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20129283, 23853484, 24573164, 30662450, 22581653)
Fulgent Genetics, Fulgent Genetics	RCV002498346	SCV002814955	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-09-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003591674	SCV004361594	uncertain significance	Cardiac arrhythmia	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1938 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is found within a highly conserved C-terminus domain (a.a. 1772-2016). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction in sodium current density in vitro (PMID: 24573164). This variant has been reported in an individual affected with Brugada syndrome (PMID: 37061847), an individual suspected of having Brugada syndrome (PMID: 20129283) and in an individual who survived sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia (PMID: 23853484). This variant has been identified in 5/280058 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV003591674	SCV004835473	uncertain significance	Cardiac arrhythmia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1938 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is found within a highly conserved C-terminus domain (a.a. 1772-2016). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction in sodium current density in vitro (PMID: 24573164). This variant has been reported in an individual affected with Brugada syndrome (PMID: 37061847), an individual suspected of having Brugada syndrome (PMID: 20129283) and in an individual who survived sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia (PMID: 23853484). This variant has been identified in 5/280058 chromosomes 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058808	SCV000090328	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.