ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs199473329
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000058808 SCV000291825 uncertain significance Brugada syndrome 2019-11-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1938 of the SCN5A protein (p.Glu1938Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs199473329, ExAC 0.009%). This variant has been reported in the literature in one patient affected with Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 68012). Experimental studies have shown that this missense change, when expressed in heterozygosity, reduces the sodium current density in vitro (PMID: 24573764). 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.

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