Submissions for variant NM_000335.5(SCN5A):c.5224G>A (p.Gly1742Arg)

gnomAD frequency: 0.00001  dbSNP: rs199473305

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183109	SCV000235519	pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	Identified in patients with Brugada syndrome referred for genetic testing at GeneDx and in published literature (PMID: 12639704, 15023552, 21147441, 21126620, 20129283, 22840528, 22984773, 25904541, 29203570, 30193851, 30972196, 31737537, 35331424); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate significantly reduced plasma membrane expression of the Nav1.5 sodium channel and reduced sodium current in vitro (PMID: 23420830, 15023552); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12639704, 28341781, 29203570, 29951135, 23420830, 22840528, 21126620, 20129283, 26111534, 22984773, 28150151, 25904541, 30203441, 15023552, 30662450, 30972196, 33221895, 31737537, 33131149, 35113650, 30193851, 21147441, 35331424, 35231055, 35675436, 35866404, 36435694, 36129056)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183109	SCV000637174	pathogenic	not provided	2023-11-19	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 1743 of the SCN5A protein (p.Gly1743Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 12639704, 15023552, 22984773, 25904541). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67967). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15023552, 23420830). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262495	SCV001440396	pathogenic	Brugada syndrome 1	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336217	SCV002642047	pathogenic	Cardiovascular phenotype	2022-11-17	criteria provided, single submitter	clinical testing	The p.G1743R pathogenic mutation (also known as c.5227G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5227. The glycine at codon 1743 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple subjects with Brugada syndrome and has been shown to segregate with disease (Takahata T et al. Life Sci., 2003 Apr;72:2391-9; Valdivia CR et al. Cardiovasc. Res., 2004 Apr;62:53-62; Hermida JS et al. Am. J. Cardiol., 2010 Dec;106:1758-62; García-Molina E et al. Clin. Genet., 2013 Jun;83:530-8; Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Yamagata K et al. Circulation, 2017 Jun;135:2255-2270). This alteration has been shown to result in impaired protein trafficking and abolished channel activity (Valdivia CR et al. Cardiovasc. Res., 2004 Apr;62:53-62; Chakrabarti S et al. Circ Arrhythm Electrophysiol, 2013 Apr;6:392-401). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002498345	SCV002809780	likely 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	2021-08-14	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058753	SCV000090273	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12639704;PMID:15023552;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.