ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1282C>T (p.Arg428Cys) (rs120074185)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046011 SCV000074024 pathogenic Long QT syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 555 of the KCNQ1 protein (p.Arg555Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs120074185, ExAC 0.008%). This variant has been reported in the literature co-segregating with disease in several families (PMID: 9386136) and in several unrelated individuals (PMID: 14998624, 19716085, 23631430) affected with long QT (LQT) syndrome. ClinVar contains an entry for this variant (Variation ID: 3126). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). Experimental studies have shown that this missense change weakens the interaction of KCNQ1 protein with PIP2 and impairs the interaction with KCNE1, resulting in the acceleration of the rundown of the maximal current of the KCNE1-KCNQ1 channel (PMID: 15746441, 19934648, 21576493, 22456477, 24681627, 25037568). In summary, this variant is a rare missense change that has been shown to co-segregate with LQT syndrome in several families and to have an impact on protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182211 SCV000234514 pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing The R555C pathogenic variant in the KCNQ1 gene has been previously reported in multiple individuals in association with LQTS (Donger et al., 1997; Nemec et al., 2003; Tester et al., 2005; Kapplinger et al., 2009; Itoh et al., 2016). Donger et al. (1997) first identified R555C in 44 individuals from three separate families and found this variant was associated with drug-induced symptoms and variable QTc intervals, often in the normal-to-borderline range. Donger et al. (1997) also reported that R555C, which is located in the C-terminal region of the KCNQ1 channel, was associated with a milder phenotype, such as a lower percentage of syncopal episodes and sudden deaths among R555C carriers, compared to carriers of other variants in the transmembrane region of the KCNQ1 channel assessed in this study. The R555C variant has also been observed in multiple individuals referred for LQTS genetic testing at GeneDx. Additionally, the R555C variant is not observed in large population cohorts (Lek et al., 2016). The R555C variant results in 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. Furthermore, functional studies have shown that KCNQ1 channels harboring R555C causes decreased binding affinity for its co-factor, PIP2, and causes impaired potassium channel function (Chouabe et al., 1997; Park et al., 2005; Matavel et al., 2010; Li et al., 2011; Barsheshet et al., 2012; Dvir et al., 2014; Coyan et al., 2014). Moreover, pathogenic/likely pathogenic missense variants at the same residue (R555S, R555H) have been reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue. In summary, R555C in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000618290 SCV000737521 pathogenic Cardiovascular phenotype 2018-05-07 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853434 SCV000996345 pathogenic Prolonged QT interval 2017-01-31 criteria provided, single submitter research The KCNQ1 Arg555Cys variant has been reported in multiple patients with Long QT syndrome (Kapplinger JD, et al., 2010; Tester DJ, et al., 2005; Paulussen AD, et al., 2005; Nemec J, et al., 2003; Donger C, et al., 1997) and has been shown to segregate with disease in 3 large families (Donger C, et al., 1997). We identified this variant in 1 proband with Long QT syndrome. The variant is present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000036; Computational tools SIFT, PolyPhen2 and MutationTaster predict this variant to be deleterious. Functional work performed on this variant has consistently shown that KCNQ1 Arg555Cys results in reduced affinity of PIP2 which is necessary for channel activity, inhibition of potassium channel activity would result in prolonged QT intervals (Barsheshet A, et al., 2012; Matavel A, et al., 2010; Park KH, et al., 2005). In summary, based on multiple reports of Long QT patients harbouring the variant, segregation data, functional studies in support of a damaging effect and rarity in the general population, we classify KCNQ1 Arg555Cys as "Pathogenic".
Color RCV001188332 SCV001355369 pathogenic Arrhythmia 2018-12-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000046011 SCV001360698 pathogenic Long QT syndrome 2019-01-28 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1663C>T (p.Arg555Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR013821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 179696 control chromosomes (gnomAD). c.1663C>T has been reported in the literature in several heterozygous individuals affected with Long QT Syndrome (e.g. Donger 1997, Imboden 2006, Yasuda 2008, Al-Hassnan 2017), where the variant was also observed to segregate with the disease in several families, although with a reduced penetrance (Donger 1997). In these families the affected individuals had a milder phenotype with later age of onset, and often normal- or borderline QTc intervals, however authors described several cases with drug-induced symptoms (Donger 1997). In a consanguineous family the variant was described in homozygosity, where the patient had an early age of onset (3 yo), experienced syncope and deafness, and had a clearly prolonged QTc on the ECG (Al-Hassnan 2017). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated compromised potassium channel function as measured by decreased "slow delayed rectifier potassium current" with an impaired PIP2 regulation (e.g. Matavel 2010, Barsheshet 2012) consistent with the established pathophysiology of LQT1. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000003274 SCV000023432 pathogenic Long QT syndrome 1 1997-11-04 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057613 SCV000089132 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:12877697;PMID:14760488;PMID:15840476;PMID:18174212;PMID:19716085;PMID:19934648;PMID:15746441;PMID:22456477). 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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