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 pathogenic not provided 2015-06-23 criteria provided, single submitter clinical testing p.Arg878Cys (CGC>TGC): c.2632 C>T in exon 16 of the SCN5A gene (NM_198056.2) The Arg878Cys mutation in the SCN5A gene has been reported in multiple individuals with Brugada syndrome or SCN5A-related arrhythmia (Zhang Y et al., 2008; Gui J et al., 2010; Kapplinger J et al., 2010). Zhang et al. reported Arg878Cys in four individuals from a large Chinese family with varying arrhythmia phenotypes. Functional studies performed indicate Arg878Cys alters sodium channel function (Zhang Y et al., 2008; Gui J et al., 2010). Arg878Cys is located in the pore forming region of domain II in the sodium channel protein type 5 subunit alpha, and this residue is highly conserved across species (Zhang Y et al., 2008). Collectively, Arg878Cys was not observed in more than 2,600 reference alleles (Zhang Y et al., 2008; Gui J et al., 2010; Kapplinger J et al., 2010). Additionally, the NHLBI ESP Exome Variant Server reports Arg878Cys was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, Arg878Cys in the SCN5A gene is interpreted as a disease-causing mutation. The variant is found in BRUGADA panel(s).
Ambry Genetics RCV000621112 SCV000737852 likely pathogenic Cardiovascular phenotype 2018-08-09 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Invitae RCV000058513 SCV001214073 likely pathogenic Brugada syndrome 2019-05-01 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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