ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2632C>T (p.Arg878Cys) (rs199473168)

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Total submissions: 4
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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.
Invitae RCV000058513 SCV001214073 likely pathogenic Brugada syndrome 2020-07-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 878 of the SCN5A protein (p.Arg878Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Brugada syndrome (PMID: 26036855, 20960618, 28341781, 28781330, 18616619). ClinVar contains an entry for this variant (Variation ID: 67744). This variant has been reported to have conflicting or insufficient data to determine the effect on SCN5A protein function (PMID: 20539757, 18616619, 20384651, 22739120). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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.

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