ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4886G>A (p.Arg1629Gln) (rs199473623)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489058 SCV000577174 pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing The R1629Q variant in the SCN5A gene has been reported previously in association with Brugada syndrome (Kapplinger et al., 2010; Zeng et al., 2013). The R1629Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R1629Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within the voltage-sensor region of the S4 segment of repeat domain IV at a position that is conserved across species. In vitro functional studies of R1629Q have demonstrated loss-of-function of cardiac sodium channel by shifting voltage dependence of inactivation, enhanced intermediate inactivation, and prolonged recovery time from inactivation (Zeng et al., 2013). Missense variants in the same codon (R1629G) and nearby residues (R1626H, R1626P, G1631D, R1632H) have been reported in the Human Gene Mutation Database in association with Brugada or Long QT syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the ACMG recommendations, R1629Q is interpreted as a known pathogenic sequence change.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709763 SCV000840066 likely pathogenic Long QT syndrome 3 2017-11-03 criteria provided, single submitter clinical testing A heterozygous likely pathogenic variant in the SCN5A gene was detected in this individuals. This variant has been previously described as disease-causing in Brugada syndrome (MIM 601144; PMID: 20129283, 24167619), an autosomal dominant cardiac conduction defect disorder. In addition, functional studies have indicated that the p.R1629Q change alters sodium channel function (PMID: 20129283). Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000058721 SCV001390526 uncertain significance Brugada syndrome 2019-05-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1629 of the SCN5A protein (p.Arg1629Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Brugada syndrome (PMID: 24167619, 20129283, 21273195). ClinVar contains an entry for this variant (Variation ID: 67937). This variant has been reported to affect SCN5A protein function (PMID: 24167619). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058721 SCV000090241 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). 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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