ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4745G>A (p.Arg1582His) (rs199473621)

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Total submissions: 4
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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 RCV000058702 SCV000090222 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.
GeneDx RCV000413021 SCV000490790 likely pathogenic not provided 2015-05-19 criteria provided, single submitter clinical testing The R1583H variant in the SCN5A gene has been reported in one individual with suspected Brugadasyndrome and was absent in >2,600 control alleles (Kapplinger et al, 2009). R1583H results in aconservative amino acid substitution at a position that is conserved across species. Missense variants inthe same residue (R1583C) and in nearby residues (L1582P, I1593M) have been reported in HGMD inassociation with SCN5A-related disorders (Stenson P et al., 2014), further supporting the functionalimportance of this region of the protein. Furthermore, the R1583H variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is abenign variant cannot be excluded.
Invitae RCV000058702 SCV000825191 uncertain significance Brugada syndrome 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1583 of the SCN5A protein (p.Arg1583His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473621, ExAC 0.01%). This variant has been reported in individuals referred for Brugada syndrome testing (PMID: 20129283, 25904541). ClinVar contains an entry for this variant (Variation ID: 67921). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455572 SCV000540287 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1-3 probands, no segregations, paralog variants in SCN1A associated with epilepsy

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