ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.151G>A (p.Ala51Thr) (rs120074177)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148553 SCV000074088 pathogenic Long QT syndrome 2020-04-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 178 of the KCNQ1 protein (p.Ala178Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs120074177, ExAC <0.01%). This variant has been reported in three individuals affected with long QT syndrome (PMID: 9024139, 22456477, 10973849) and in one patient referred to long QT genetic testing (PMID: 19716085). This variant is also known in the literature as A49T. ClinVar contains an entry for this variant (Variation ID: 53061). One experimental study has shown that this missense variant moderately reduces current density, peak tail current density, and shifts the voltage dependent of channel activation in vitro (PMID: 24912595). A different missense substitution at this codon (p.Ala178Pro) is reported to be deleterious (PMID: 17470695). This indicates that the alanine residue is important for KCNQ1 protein function. In summary, this variant is a rare missense change that has been reported in patients affected with longQT syndrome, and to affected protein function in vitro. In addition, this variant is located in a residue important for protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182081 SCV000234384 pathogenic not provided 2021-05-04 criteria provided, single submitter clinical testing Identified in several patients with LQTS referred for genetic testing at GeneDx, and in published literature (Tanaka et al., 1997; Splawski et al., 2000; Jons et al., 2009; Kapplinger et al., 2009; Kwok et al., 2018); Reported in ClinVar (ClinVar Variant ID# 53061; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant severely disrupted channel trafficking (Harmer et al., 2014; Mousavi et al., 2015); This variant is associated with the following publications: (PMID: 28991257, 26546361, 25705178, 24912595, 22456477, 19716085, 19490272, 10973849, 12388934, 9024139, 25637381, 22378279, 30530868)
Ambry Genetics RCV000244422 SCV000320309 likely pathogenic Cardiovascular phenotype 2015-09-10 criteria provided, single submitter clinical testing The p.A178T variant (also known as c.532G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 532. The alanine at codon 178 is replaced by threonine, an amino acid with similar properties. <span style="font-family:arial,sans-serif; font-size:10pt">This alteration has been detected inindividuals reported to havelong QT syndrome (TanakaT et al.<span style="font-family:arial,sans-serif">Circulation.1997; 95(3):565-7 (reported asAla49Thr);JonsC et al.<span style="font-family:arial,sans-serif">J<span style="font-family:arial,sans-serif; font-size:10pt">Cardiovasc<span style="font-family:arial,sans-serif; font-size:10pt"><span style="font-family:arial,sans-serif; font-size:10pt">Electrophysiol<span style="font-family:arial,sans-serif; font-size:10pt">.<span style="font-family:arial,sans-serif; font-size:10pt">2009; 20(8):859-65;KapplingerJD et al.<span style="font-family:arial,sans-serif">Heart Rhythm.2009;6(9):1297-303).Thisalterationhas also been seen inexomecohorts, but cardiovascular history was not provided (AmendolaLM et al.<span style="font-family:arial,sans-serif">Genome Res. 2015;25(3):305-15). Inone study, thisalteration wasdetected in compoundheterozygositywith aframeshiftalteration in a severely affected child, while relatives who wereheterozygous for thesealterationswere unaffected. In the same study,the p.A178T alterationwas reported to have moderate impact on channel trafficking and function and moderate dominant negative effect(Harmer SC et al.<span style="font-family:arial,sans-serif; font-size:10pt">Biochem<span style="font-family:arial,sans-serif; font-size:10pt">J.<span style="font-family:arial,sans-serif; font-size:10pt">2014; 462(1):133-42).In addition,another alteration affecting this amino acid, p.A178P(c.532G>C), hasalso been reported inassociationwith long QTsyndrome (Wang Q et al.<span style="font-family:arial,sans-serif">NatGenet.1996; 12(1):17-23 (reported asA49P))<span style="font-family:arial,sans-serif; font-size:10pt">.This variant was previously reported in the SNPDatabase as rs120074177. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13000) total alleles studied and 0.01% (1/8598) European American alleles. This variant was not reported in population-based cohorts in the following databases:1000 Genomes Project.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001028063 SCV001369915 likely pathogenic Long QT syndrome 1 2020-02-27 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1_MOD,PM2,PS4_SUP,PP3.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258060 SCV001434891 likely pathogenic Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1 2019-08-19 criteria provided, single submitter clinical testing This c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene has been reported in patients with Long QT syndrome (PMID: 9024139, 22456477, 10973849). This variant has an ultra-low minor allele frequency in the gnomAD database (1/248870). The Ala178 residue is highly conserved and multiple computational algorithms predict a deleterious effect of the p.Ala178Thr change. In vitro functional studies suggest this variant disrupts channel trafficking (PMID: 24912595). Therefore, the c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene is classified as likely pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057692 SCV000089211 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:9024139;PMID:19716085;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148553 SCV000190266 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV001028063 SCV001190839 pathogenic Long QT syndrome 1 2020-02-05 no assertion criteria provided clinical testing

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