Submissions for variant NM_000335.5(SCN5A):c.3691C>T (p.Arg1231Trp)

dbSNP: rs199473207

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183042	SCV000235451	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing	Identified in one family with idiopathic ventricular fibrillation, who also harbored the T1620M variant on the same SCN5A allele (in cis); functional studies suggested that T1620M is probably disease-causing and that R1232W is a possible rare polymorphism because it did not alter the current voltage activity of the sodium channel (Chen et al., 1998); Another functional study demonstrated that the presence of a positively charged amino acid at position 1232 was essential for the proper trafficking of the sodium channel protein to the cell surface, and that the double mutant (R1232W/T1620M) showed abnormal functional sodium channel expression (Baroudi et al., 2002); However, Makita et al. (2008) reported R1232W/T1620M did not affect protein trafficking in their expression studies, contradicting the functional effect reported by Baroudi et al. (2002); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29728395, 12454206, 24136861, 25904541, 16864729, 14961552, 11417215, 11013131, 19251209, 20129283, 26173111, 11786529, 21321465, 30193851, 18503232, 9521325, 33131149)
Color Diagnostics, LLC DBA Color Health	RCV001842342	SCV001352308	uncertain significance	Cardiac arrhythmia	2020-11-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1232 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 that this variant does not adversely affect protein trafficking and channel function (PMID: 9521325, 18503232). This variant has been reported in a family affected with idiopathic ventricular fibrillation (PMID: 9521325). All eight affected individuals from this family carried this variant and p.Thr1620Met in cis. This variant has been reported in an individual affected with cardiac conduction disease (PMID: 19251209) and two individuals affected with Brugada syndrome (PMID: 20129283, 21321465). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183042	SCV001570375	uncertain significance	not provided	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1232 of the SCN5A protein (p.Arg1232Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 9521325, 19251209, 20129283, 21321465, 26173111, 30193851, 33797273). ClinVar contains an entry for this variant (Variation ID: 67813). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 9521325, 11013131, 11417215, 11786529, 18503232). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000183042	SCV002542037	uncertain significance	not provided	2021-07-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345369	SCV002621440	uncertain significance	Cardiovascular phenotype	2018-12-28	criteria provided, single submitter	clinical testing	The p.R1232W variant (also known as c.3694C>T), located in coding exon 20 of the SCN5A gene, results from a C to T substitution at nucleotide position 3694. The arginine at codon 1232 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the transmembrane-spanning DIII-S1/S2 domain. This variant was detected in an individual with ECG findings consistent with Brugada syndrome (BrS); testing in family members revealed three symptomatic carriers and one unaffected carrier, who was young at the time of cardiac evaluation (Selga E et al. PLoS ONE, 2015 Jul;10:e0132888). In addition, this variant was described in a BrS case with a p.R1232W SCN5A variant also detected (Nakajima T et al. Int Heart J, 2011;52:27-31). It has also been reported in cis with an SCN5A p.T1620M variant in multiple affected individuals from one family with idiopathic ventricular fibrillation; however, functional and localization studies in R1232W/T1620M cells have shown conflicting results (Chen Q et al. Nature, 1998 Mar;392:293-6; Wan X et al. J. Mol. Cell. Cardiol., 2000 Oct;32:1873-84; Baroudi G et al. Circ. Res., 2002 Jan;90:E11-6; Makita N et al. Circ. J., 2008 Jun;72:1018-9). An alternate amino acid substitution at this position, p.R1232Q, was also reported in Brugada syndrome cohorts where clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Conte G et al. J. Cardiovasc. Electrophysiol., 2014 May;25:514-519; Conte G et al. J. Am. Coll. Cardiol., 2014 Jun;63:2272-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058588	SCV000090108	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:9521325;PMID:19251209;PMID:20129283;PMID:21321465). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneReviews	RCV000144030	SCV000188923	not provided	Brugada syndrome 1		no assertion provided	literature only