ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1946G>A (p.Cys649Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1380959630
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001843127 SCV001348019 uncertain significance Cardiac arrhythmia 2022-06-09 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tyrosine at codon 649 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248298 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.
Invitae RCV003541474 SCV002138425 uncertain significance not provided 2021-11-02 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 922452). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 649 of the SCN5A protein (p.Cys649Tyr).
Ambry Genetics RCV002411688 SCV002719331 uncertain significance Cardiovascular phenotype 2020-04-29 criteria provided, single submitter clinical testing The p.C649Y variant (also known as c.1946G>A), located in coding exon 12 of the SCN5A gene, results from a G to A substitution at nucleotide position 1946. The cysteine at codon 649 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the DI/DII interdomain linker region of the protein. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002483992 SCV002789546 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 2021-08-25 criteria provided, single submitter clinical testing

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