Submissions for variant NM_000335.5(SCN5A):c.2632C>T (p.Arg878Cys)

dbSNP: rs199473168

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183008	SCV000235414	likely pathogenic	not provided	2020-07-28	criteria provided, single submitter	clinical testing	Reported to segregate with varying arrhythmia phenotypes in four individuals from one family (Zhang et al., 2008); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 67744; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22840528, 28449774, 18616619, 20539757, 27381756, 20960617, 24136861, 17368591, 25399282, 26036855, 30476647, 29233994, 30232268, 22739120, 28781330, 28341781, 20129283, 24055942, 30662450, 33131149)
Ambry Genetics	RCV000621112	SCV000737852	likely pathogenic	Cardiovascular phenotype	2018-08-09	criteria provided, single submitter	clinical testing	The p.R878C variant (also known as c.2632C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2632. The arginine at codon 878 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with Brugada syndrome and sick sinus syndrome (Savastano S et al. Heart Rhythm, 2014 Jul;11:1176-83; Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Crotti L et al. J. Am. Coll. Cardiol., 2012 Oct;60:1410-8; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). Segregation with disease has been reported in some families; however, clinical information was limited and some family members had additional variants (Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23; Bissay V et al. Eur. J. Hum. Genet., 2016 Mar;24:400-7; Van Malderen SCH et al. Circ. J., 2017 Dec;82:53-61). This variant is located in the S5-S6 pore-forming segment of the DII domain, and functional studies have demonstrated loss of sodium channel function despite proper localization in the cell membrane (Gui J et al. PLoS ONE, 2010 Jun;5:e10985; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183008	SCV001214073	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 878 of the SCN5A protein (p.Arg878Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 18616619, 20960618, 26036855, 28341781, 28781330). ClinVar contains an entry for this variant (Variation ID: 67744). 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: 18616619, 20384651, 20539757, 22739120). This variant disrupts the p.Arg878 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 25904541, 30193851; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058513	SCV000090033	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:18616619;PMID:20129283;PMID:20539757;PMID:20960617). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.