ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1604G>A (p.Arg535Gln) (rs199473121)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638649 SCV000760187 uncertain significance Brugada syndrome 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 535 of the SCN5A protein (p.Arg535Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199473121, ExAC 0.002%). This variant has been reported in several individuals either affected with long QT syndrome or with a suspicion of this condition (PMID: 24349418, 19716085). ClinVar contains an entry for this variant (Variation ID: 67672). Experimental studies have shown that this missense change results in a sodium channel with an increased inactivation time leading to a persistent sodium current and a tendency to prolonged action potential duration (PMID: 24349418). 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000677695 SCV000803843 pathogenic Long QT syndrome 3 2016-08-03 criteria provided, single submitter clinical testing
Mendelics RCV000987228 SCV001136477 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001189141 SCV001356355 uncertain significance Arrhythmia 2019-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193949 SCV001363137 uncertain significance not specified 2019-08-28 criteria provided, single submitter clinical testing Variant summary: SCN5A c.1604G>A (p.Arg535Gln) results in a conservative amino acid change located in the intracellular linker region between DI and DII in the alpha-subunit of a voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248026 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1604G>A, has been reported in the literature in individuals affected with long QT syndrome 3 or atrial fibrillation (Kapplinger_2009, Fatima_2013, Van Driest SL_2016, Gregers_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Fatima_2013 reports that the variant of LQTS-3 CM have a defective sodium channel which takes longer time for inactivation leading to persistent sodium current and the tendency for prolongation of action potential duration. Two ClinVar submissions (evaluation after 2014) cite the variant once as pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058435 SCV000089955 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). 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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