ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.139C>T (p.Arg47Cys) (rs199472696)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046072 SCV000074085 pathogenic Long QT syndrome 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 174 of the KCNQ1 protein (p.Arg174Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199472696, ExAC <0.01%). This variant has been reported in the literature in multiple unrelated individuals affected with long QT syndrome (PMID: 9386136, 23392653, 23130128, 15840476, 11668638, 19716085). ClinVar contains an entry for this variant (Variation ID: 53058). Experimental studies have shown that this missense change significantly decreases KCNQ1 protein function (PMID: 9312006, 19934648). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182078 SCV000234381 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing The R174C pathogenic variant in the KCNQ1 gene has been published multiple times in association with LQTS (Donger et al., 1997; Splawski et al., 2000; Tester et al., 2005; Kapplinger et al., 2009; Couderc et al., 2012; Giudicessi et al., 2013; Burgos et al., 2016; Miyazaki et al., 2016). In addition, this variant was identified in a Turkish female infant with JLNS who presented with intrauterine bradycardia; bilateral congential deafness and a prolonged QTc of 530 ms was diagnosed at 33 days old (Uysal et al., 2017). This patient also harbored a pathogenic c.477+1 G>A variant on the other KCNQ1 allele (in trans) (Uysal et al., 2017). R174C has also been identified in multiple other unrelated individuals referred for LQTS genetic testing at GeneDx, and has been found to segregate with LQTS phenotype in several families. The R174C variant is not observed in large population cohorts (Lek et al., 2016). R174C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies demonstrate that the R174C variant impairs potassium channel regulation and function (Chouabe et al., 1997; Matavel et al., 2010). Finally, other pathogenic or likely pathogenic missense variants in nearby residues (W176R, A178T, A178P, G179S, G179A) and in the same residue (R174H, R174L) have been reported in the Human Gene Mutation Database or at GeneDx in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein.
Integrated Genetics/Laboratory Corporation of America RCV000587627 SCV000695990 pathogenic Long QT syndrome 1 2016-02-01 criteria provided, single submitter clinical testing Variant summary: The c.520C>T (p.R174C) in KCNQ1 gene is a missense variant that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is present in the control population dataset of ExAC at a low frequency (0.0008%) which does not exceed the maximum allele frequency for a pathogenic KCNQ1 variant (0.01%). This variant has been reported in the literature in multiple affected individuals presented with elongated QTc interval, including one homozygous pt with severe arrhythmic presentation. Other alterations of the same codon, p.R174H, p.R174L and p.R174P have been reported in pts with LQTS. Functional studies showed p.R174C alters the normal channel activity. In addition, several reputable databases/clinical laboratories classified the variant as Pathogenic. Therefore, this variant was classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057689 SCV000089208 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:9386136;PMID:11668638;PMID:15840476;PMID:19716085;PMID:19934648). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000046072 SCV000804994 pathogenic Long QT syndrome 2015-09-10 no assertion criteria provided clinical testing

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