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 Health, Inc RCV001192188 SCV001360190 likely pathogenic Arrhythmia 2021-02-24 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 224 in the extracellular linker region of the KCNQ1 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). A functional study has shown that the mutant channel significantly reduces total activating and deactivating currents (PMID: 33141630). This variant has been reported in many individuals affected with long QT syndrome (PMID: 19716085, 19841298, 33141630) and has been reported to segregate with disease in one family (PMID: 19841298). In particular, this variant has been reported to be a common cause of long QT syndrome in the Amish population with 34/88 (38.6%) of carriers versus 3/54 (5.5%) of non-carriers showing clinical evidence of long QT syndrome (P=0.0006) (PMID: 33141630). This study has suggested that the phenotypes associated with this variant appear to be mild. While this variant is observed at 1/45 frequency in the Amish population (PMID: 33141630), it is rare in the general population and has been identified in 1/248566 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV000754820 SCV001390833 pathogenic Long QT syndrome 2020-10-21 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 multiple individuals affected with long QT syndrome and has been considered as a founder variant in the Amish population (PMID: 19841298, external communication). ClinVar contains an entry for this variant (Variation ID: 67096). This variant has been reported to affect KCNQ1 protein function (external communication). For these reasons, this variant has been classified as Pathogenic.
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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