Submissions for variant NM_000335.5(SCN5A):c.4219G>A (p.Gly1407Arg)

dbSNP: rs137854612

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183190	SCV000235608	pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Published functional studies indicated mutant channels failed to produce inward sodium currents despite normal surface localization, suggesting a gating defect (PMID: 20539757); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27766308, 27381756, 28150151, 17368591, 26154754, 28018021, 28341781, 32569262, 31993492, 30147658, 34219138, 34436362, ONeill2021, 34649698, 34814702, 34147702, 33131149, 19251209, 30662450, 20031634, 30193851, 30203441, 37745129, 20129283, 20539757, 11748104, 14523039)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183190	SCV000637149	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1408 of the SCN5A protein (p.Gly1408Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with first-degree heart block as a dominant trait and with sick sinus syndrome (SSS) as a recessive trait and Brugada syndrome (BrS) and isolated cardiac conduction disease in a large multigenerational family (PMID: 11748104, 14523039, 20129283). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9395). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002326672	SCV002630345	pathogenic	Cardiovascular phenotype	2023-03-16	criteria provided, single submitter	clinical testing	The p.G1408R pathogenic mutation (also known as c.4222G>A), located in coding exon 22 of the SCN5A gene, results from a G to A substitution at nucleotide position 4222. The glycine at codon 1408 is replaced by arginine, an amino acid with dissimilar properties, and is located in the DIII-S5/S6 region. This variant (referred to as G1406R) has been reported to segregate either with Brugada syndrome (BrS) or cardiac conduction disease in one large family (Kyndt F et al. Circulation, 2001 Dec;104:3081-6). In another family, this variant segregated with sick sinus syndrome in three siblings with a second SCN5A variant, while individuals with only p.G1408R had heart block or normal ECGs (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28). This variant has also been detected in several unrelated individuals from a BrS cohort (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). In vitro assays have reported this variant to result in channels with low-to-no detectable current despite normal protein trafficking (Kyndt F et al. Circulation, 2001 Dec;104:3081-6; Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28Gui J et al. PLoS ONE, 2010 Jun;5:e10985). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002496318	SCV002805675	pathogenic	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	2022-03-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000183190	SCV003916427	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SCN5A: PM1, PM2, PS4:Moderate, PP1, PP3, PP4, PS3:Supporting
All of Us Research Program, National Institutes of Health	RCV003996085	SCV004839381	pathogenic	Congenital long QT syndrome	2023-12-07	criteria provided, single submitter	clinical testing	The c.4222G>A (p.Gly1408Arg) variant in the SCN5A gene replaces glycine with arginine in codon 1408 of the SCN5A protein. This variant has been reported in individuals with Brugada syndrome and segregated with disease in members of a family (PMID: 11748104, 20129283, 36516610). Functional assays have shown disruptive impact of this variant on the protein (PMID: 11748104, 20539757). Computational models predict a deleterious impact of this variant on the translated protein. ClinVar contains an entry for this variant (Variation ID: 9395). This variant is absent in the population database (gnomAD). Based on the available evidence this variant is classified as pathogenic.
OMIM	RCV000009995	SCV000030216	pathogenic	Sick sinus syndrome 1	2003-10-01	no assertion criteria provided	literature only
OMIM	RCV000009996	SCV000030217	pathogenic	Brugada syndrome 1	2003-10-01	no assertion criteria provided	literature only
OMIM	RCV000009997	SCV000030218	pathogenic	Conduction system disorder	2003-10-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058649	SCV000090169	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11748104;PMID:14523039;PMID:19251209;PMID:20129283;PMID:20539757). 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	RCV000058649	SCV000805034	likely pathogenic	Brugada syndrome	2017-01-13	no assertion criteria provided	clinical testing