Submissions for variant NM_000335.5(SCN5A):c.3715G>C (p.Glu1239Gln)

gnomAD frequency: 0.00003  dbSNP: rs199473211

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001256851	SCV000545034	uncertain significance	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1240 of the SCN5A protein (p.Glu1240Gln). This variant is present in population databases (rs199473211, gnomAD 0.007%). This missense change has been observed in individuals with Brugada syndrome and/or SCN5A-related conditions (PMID: 11901046, 30203441, 37937776). This variant is also known as c.3715G>C, p.Glu1239Gln. ClinVar contains an entry for this variant (Variation ID: 67818). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842345	SCV000905122	uncertain significance	Cardiac arrhythmia	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1240 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown this variant does not affect the channel function (PMID: 30891416). This variant has been reported in an individual affected with Brugada syndrome (PMID: 11901046). This variant has been reported in an individual affected with unexplained sudden cardiac arrest and recurrent ventricular tachycardia and ventricular fibrillation episodes (PMID: 30891416). However, no Brugada ECG pattern was observed in this individual or five other asymptomatic family member carriers. This variant has also been identified in 10/251026 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256851	SCV001433339	uncertain significance	not provided	2019-07-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504973	SCV002814359	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	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162458	SCV003903606	likely benign	Cardiovascular phenotype	2023-02-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV001842345	SCV004824092	uncertain significance	Cardiac arrhythmia	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1240 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect the channel function (PMID: 30891416). This variant has been reported in an individual affected with Brugada syndrome (PMID: 11901046). This variant has aslo been reported in an individual affected with unexplained sudden cardiac arrest and recurrent ventricular tachycardia and ventricular fibrillation episodes (PMID: 30891416). However, no Brugada ECG pattern was observed in this individual or five other asymptomatic family member carriers. This variant has also been identified in 10/251026 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	RCV000058593	SCV000090113	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11901046). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678843	SCV000805032	likely pathogenic	not specified	2016-04-18	no assertion criteria provided	clinical testing