ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1235G>A (p.Arg412Gln) (rs199472794)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182207 SCV000234510 likely pathogenic not provided 2021-05-26 criteria provided, single submitter clinical testing Reported in one individual with sudden cardiac arrest and a clinical diagnosis of Jervell and Lange-Nielsen syndrome and in individuals referred for LQTS genetic testing at GeneDx and in published literature (Kapplinger et al., 2009; Burns et al., 2016; Jimenez-Jaimez et al., 2017); Reported in ClinVar (ClinVar Variant ID# 67042; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19716085, 28566242, 27920829)
Invitae RCV000556413 SCV000627381 uncertain significance Long QT syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 539 of the KCNQ1 protein (p.Arg539Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg539 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23098067, 23251633, 23631430, 24681627, 25559286). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584804 SCV000692511 likely pathogenic Long QT syndrome 1 2017-03-14 criteria provided, single submitter research The KCNQ1 Arg539Gln has been reported previously in a case control study of 2500 patients referred for long QT genetic testing (Kapplinger JD, et al., 2009), as well as a long QT patient (Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust ClinVar: SCV000089124). Interestingly, another rare variant at this position (KCNQ1 Arg539Trp) has been classified as pathogenic; suggesting that an amino acid substitution at this site may not be tolerated. We have identified this KCNQ1 Arg539Gln variant in one long QT case, and the variant was found to segregate to another affected family member. The variant is absent in the 1000 genomes project (, as well as the Exome Aggregation Consortium dataset ( Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. This variant was discussed at our multidisciplinary pathogenicity meeting and based on rarity in the general population, pathogenic classification of another amino acid substitution at the same position, our familial data, in silico tools supportive of a deleterious effect and because the proband has a typical LQT1 phenotype which is known to be caused by genetic variation in only the KCNQ1 gene, we classify KCNQ1 Arg539Gln as "likely pathogenic".
Ambry Genetics RCV000619224 SCV000737705 uncertain significance Cardiovascular phenotype 2016-08-29 criteria provided, single submitter clinical testing The p.R539Q variant (also known as c.1616G>A), located in coding exon 13 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1616. The arginine at codon 539 is replaced by glutamine, an amino acid with highly similar properties. In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). Another alteration affecting this amino acid (p.R539W, c.1615C>T) has been previously reported in association with LQTS (Chouabe C et al. Cardiovasc Res. 2000;45(4):971-80). This variant was previously reported in the SNPDatabase as rs199472794. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6473 samples (12946 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV001182571 SCV001348066 likely pathogenic Arrhythmia 2019-05-28 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057605 SCV000089124 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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