Submissions for variant NM_000335.5(SCN5A):c.128G>A (p.Arg43Gln)

gnomAD frequency: 0.00005  dbSNP: rs199473047

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654189	SCV000637075	uncertain significance	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 43 of the SCN5A protein (p.Arg43Gln). This variant is present in population databases (rs199473047, gnomAD 0.03%). This missense change has been observed in individual(s) with atrioventricular block and ventricular tachycardia (PMID: 18848812, 19716085). ClinVar contains an entry for this variant (Variation ID: 67654). 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. 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	RCV001842274	SCV001357886	uncertain significance	Cardiac arrhythmia	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 43 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect baseline kinetics of the sodium current but disrupts the sodium channel function when treated with lidocaine (PMID: 18848812). However, clinical relevance of this finding is unknown. This variant has been reported in a family affected with long QT syndrome, who also carried a variant in the KCNH2 gene that adversely affected the potassium channel function in an experimental study (PMID: 18848812). This variant has also been reported in an individual suspected of having long QT genetic testing (PMID: 19716085), and in another individual suspected of having epilepsy (PMID: 31696929). This variant has been identified in 12/247486 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.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319178	SCV003932414	uncertain significance	Hypertrophic cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298118	SCV003997036	likely benign	Cardiovascular phenotype	2023-04-20	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	RCV001842274	SCV004815099	uncertain significance	Cardiac arrhythmia	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 43 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). A functional study has shown that this variant does not affect baseline kinetics of the sodium current but disrupts the sodium channel function when treated with lidocaine (PMID: 18848812). This variant has been reported in an individual affected with Brugada syndrome (PMID: 30690642), in an individual suspected of having long QT syndrome (PMID: 19716085), and in another two individuals suspected of having epilepsy (PMID: 31696929). This variant has also been reported in an individual with prolonged QT interval, who also carried a pathogenic variant in the KCNH2 gene that could explain the observed phenotype (PMID: 18848812). This variant has been identified in 12/247486 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	RCV000058412	SCV000089932	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18848812;PMID:18984535;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.