ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4892G>A (p.Arg1631His) (rs199473286)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058723 SCV000090243 not provided Cardiac conduction defect, nonspecific no assertion provided literature only This variant has been reported in the following publications (PMID:14523039;PMID:20384651;PMID:20539757).
GeneDx RCV000519341 SCV000616867 pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing The R1632H pathogenic variant in the SCN5A gene has been reported in association with sick sinus syndrome (SSS) (Benson et al., 2003; Robyns et al., 2014). Benson et al. (2003) reported this variant in a patient with SSS who also harbored an additional variant in SCN5A, the R1632H variant was paternally inherited and the father was diagnosed with first degree heart block. Robyns et al. (2014) also reported a patient who is compound heterozygous for two variants in the SCN5A gene. Although the R1632H results in a conservative amino acid substitution, the R1632 residue is highly conserved across species. Additionally, functional studies reported that the R1632H variant results in a loss of function, with R1632H mutant channels demonstrating slower recovery from inactivation that likely results in reduced channel availability in cardiomyocytes (Benson et al., 2003; Gui et al. 2010). A missense variant in the same residue (R1632C) has been reported in HGMD in association with Brugada syndrome (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Furthermore, the R1632H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000553192 SCV000637165 uncertain significance Brugada syndrome 2019-01-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1632 of the SCN5A protein (p.Arg1632His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473286, ExAC 0.01%). This variant has been reported in individuals affected with Brugada syndrome (PMID: 28781330), and sick sinus syndrome (PMID: 14523039). This variant has been reported to segregate with sick sinus syndrome in a single family where individuals carrying this variant in the compound heterozygous state with p.Met848Leu displayed a more severe phenotype (PMID: 24948852). Experimental studies have shown that this missense change disrupts the function of SCN5A (PMID: 20384651,20539757). In summary, this variant segregates with disease in a single family and disrupts protein function in vitro. However, there is not enough evidence to prove conclusively that it causes disease. For these reasons, this change has been classified as a Variant of Uncertain Significance.

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