ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4613G>A (p.Cys1538Tyr)

dbSNP: rs770780069
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003541309 SCV001407754 uncertain significance not provided 2019-11-06 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN5A-related conditions. This variant is present in population databases (rs770780069, ExAC 0.001%). This sequence change replaces cysteine with tyrosine at codon 1539 of the SCN5A protein (p.Cys1539Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.
Ambry Genetics RCV002339646 SCV002636582 uncertain significance Cardiovascular phenotype 2020-09-16 criteria provided, single submitter clinical testing The p.C1539Y variant (also known as c.4616G>A), located in coding exon 26 of the SCN5A gene, results from a G to A substitution at nucleotide position 4616. The cysteine at codon 1539 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the transmembrane DIV-S1 domain. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224534 SCV003920439 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2021-03-30 criteria provided, single submitter clinical testing SCN5A NM_198056.2 exon 27 p.Cys1539Tyr (c.4616G>A): This variant has not been reported in the literature but is present in 0.0008% (1/112994) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-38595967-C-T). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health RCV004004859 SCV004815745 uncertain significance Cardiac arrhythmia 2023-10-23 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tyrosine at codon 1539 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 2/249246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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