ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.290C>T (p.Thr97Met) (rs199472706)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000754820 SCV000882470 likely pathogenic Long QT syndrome 2017-12-21 criteria provided, single submitter clinical testing The c.671C>T variant in codon 224 (exon 5) of the potassium voltage-gated channel subfamily Q member 1 gene, KCNQ1, results in the substitution of Threonine to Methionine. Missense variants in the KCNQ1 gene are known to cause autosomal dominant hereditary long QT syndrome 1 (also known as Romano-Ward syndrome) and autosomal recessive Jervell and Lange-Nielsen syndrome (24667783, 15840476, 27761162). The c.671C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases, however the c.671C>T variant was previously reported in a patient with long QT syndrome (19716085 Multiple lines of computational evidence (MutationTaster, FATHMM, GERP, MetaSVM, MetalR, Provean, LRT, SIFT) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. The c.671C>T variant is located within a transmembrane region of the protein that has minimal benign variation among individuals in population databases and in the literature (27761162, 17227916). ACMG criteria = PS4, PM1, PM2, PP3
Color RCV001192188 SCV001360190 uncertain significance Arrhythmia 2019-05-11 criteria provided, single submitter clinical testing
Invitae RCV000754820 SCV001390833 uncertain significance Long QT syndrome 2019-09-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 224 of the KCNQ1 protein (p.Thr224Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (PMID: 19841298), in an individual with drug-induced torsades de pointes (PMID: 24223155), and in an individual who was referred for long QT genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67096). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000057729 SCV000089248 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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