Submissions for variant NM_000335.5(SCN5A):c.53G>A (p.Arg18Gln)

gnomAD frequency: 0.00004  dbSNP: rs41311087

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041626	SCV000065322	uncertain significance	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766749	SCV000520830	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing	Identified in patients with Brugada, LQTS, short-coupled variant of Torsades de Pointes, and sudden unexplained death, but no segregation studies are available (Amin et al., 2011; Kapplinger et al., 2010; Kapplinger et al., 2009; Kajiyama et al., 2020; Farrugia et al., 2015); Published functional studies demonstrated that the variant was comparable to wild-type with regards to whole-cell currents, steady state activation and inactivation, and recovery from inactivation, exhibiting no loss-of-function characteristics typically associated with Brugada syndrome pathogenic variants (Gutter et al., 2013); LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants, and this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24324440, 19716085, 20129283, 21273195, 23805106, 32153684, 26164358, 22581653, 33131149, 29709244)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000041626	SCV000748021	uncertain significance	not specified	2017-07-03	criteria provided, single submitter	clinical testing
Invitae	RCV000766749	SCV000942240	uncertain significance	not provided	2023-12-31	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 18 of the SCN5A protein (p.Arg18Gln). This variant is present in population databases (rs41311087, gnomAD 0.03%). This missense change has been observed in individual(s) with sudden unexplained death, suspected or definite Brugada syndrome, or suspected Long QT syndrome (PMID: 19716085, 20129283, 21273195, 26164358, 32153684). ClinVar contains an entry for this variant (Variation ID: 48306). 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 does not substantially affect 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.
Color Diagnostics, LLC DBA Color Health	RCV001841609	SCV001356414	uncertain significance	Cardiac arrhythmia	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 18 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 has no significant impact on channel function in transfected cells (PMID: 23805106). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195), short coupled variant of Torsades de Pointes (ScTdP) (PMID: 32153684), or suspected of having long QT syndrome (PMID: 19716085), and Brugada syndrome (PMID: 26164358). This variant has been identified in 20/279956 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.
Ambry Genetics	RCV002345328	SCV002652186	likely benign	Cardiovascular phenotype	2021-09-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058779	SCV000090299	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.