ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.140G>A (p.Arg47His) (rs199472697)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000984322 SCV000845652 pathogenic Long QT syndrome 1 2017-09-29 criteria provided, single submitter clinical testing This variant has been reported in multiple patients with LQTS (1. Denjoy et al. (1999) Arch Mal Coeur Vaiss. 92(5):557-63; Splawski et al. (2000) Circulation. 102(10):1178-85; Shimizu et al. (2004) J Am Coll Cardiol. 44(1):117-25; Moss et al. (2007) Circulation. 115(19):2481-9; Kapplinger et al. (2009) Heart Rhythm. 6(9):1297-303; Lupoglazoff et al J Am Coll Cardiol. 2004 Mar 3;43(5):82630; ClinVar variation ID 53059), and has been detected in a single individual in control populations (ExAC database 1/16484 alleles). Other variants at the same amino acid residue have also been reported in association with LQTS: p.Arg174Cys (pubmed: 9386136, 15840476, 19716085, 19934648, 9312006, 11668638); p.Arg174Leu (pubmed: 21956039); p.Arg174Pro (pubmed: 16414944). This variant occurs in the Transmembrane/Linker/Pore region of KCNQ1. Variants found in this region have been shown to have a high probability of pathogenicity (Kapa et al. Circulation. 2009 Nov 3; 120(18): 1752–1760). In silico analysis predicts pathogenicity (SIFT; PolyPhen; Mutation Taster; LRT, FATHMM; MutationAssessor) but these predictions have not been confirmed by published functional studies. The affected amino acid residue is highly conserved across species.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000984322 SCV001132518 likely pathogenic Long QT syndrome 1 2017-11-08 criteria provided, single submitter curation
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000223741 SCV001433431 likely pathogenic not provided 2019-07-31 criteria provided, single submitter clinical testing
Invitae RCV001386000 SCV001586070 pathogenic Long QT syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 174 of the KCNQ1 protein (p.Arg174His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199472697, ExAC 0.006%). This variant has been observed in several individuals affected with long QT syndrome (PMID: 14998624, 23130128, 10973849, 19716085, Invitae). ClinVar contains an entry for this variant (Variation ID: 53059). Experimental studies have shown that this missense change leads to decreased KCNQ1 cell surface expression and trafficking activity (PMID: 29532034). Variants that disrupt the p.Arg174 amino acid residue in KCNQ1 have been observed in affected individuals (PMID: 9386136, 23392653, 23130128, 15840476). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057690 SCV000089209 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:10367071;PMID:10973849;PMID:14998624;PMID:19716085;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223741 SCV000280155 likely pathogenic not provided 2012-02-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Arg174His Based on the information reviewed below, we classify it as likely disease causing. This variant has previously been reported multiple times, in ~7 unrelated individuals with LQTS (it is unclear if there is any overlap in individuals reported in the following papers). Splawski et al. (2000) reported it for the first time in a proband with LQTS. Shimizu et al. (2004) described its effects in 1 Japanese family. Lupoglazoff et al. (2004) reported it in a neonate with sinus bradycardia and prolonged QT of 500 msec. Moss et al. (2007) reported it in 2 unrelated families in the U.S. International/Netherlands/Japanese LQTS Registries. Kapplinger et al. (2009) reported it in one individual tested for LQTS at Familion. In 2009, clinicians from Kaiser San Diego and UCSD reported it in an abstract at ASHG as a homozygous mutation in a neonate with Jervell and Lange-Nielsen syndrome, whose family members (maternal and paternal) had LQTS. There is no known published segregation data. We do have segregation data within a family at our center, however, and the variant tracks with disease. Other variants at this same amino acid residue have also been reported in association with LQTS according to HGMD: p.Arg174Cys, p.Arg174Leu, p.Arg174Pro. This is a conservative amino acid change, resulting in the replacement of a positively charged arginine with a positively charged histidine, but the side chains are very different in shape. According to, Arg174 is entirely conserved across 32 paralogue channel proteins. Variation at nearby residues (+10 amino acids) has been associated with LQTS, which supports the functional importance of this region of the protein: p.Gly168Arg, p.Thr169Arg, Glu170Gly, p.Val172Met, p.Val173Asp, p.Ala178Pro, p.Ala178Thr, p.Gly179Ser, p.Lys183Arg, p.Lys183Met, p.Tyr184His, p.Tyr184Ser (HGMD professional version as of January 17, 2014). Arg174 is in a transmembrane spanning region of KCNQ1, and such variants have been shown to have a higher likelihood of being deleterious than variants in other regions of the protein (Kapa et al. 2009). In silico analysis with PolyPhen-2 ( predicts the variant to be “Probably Damaging” with a score of 1.0 In total the variant has not been seen in over 7500 published controls and individuals from publicly available population datasets. Kapplinger et al. (2009) did not observe it in 1300 ethnically diverse controls: 47% Caucasian, 26% African-American, 11% Hispanic, 10% Asian, 6% unknown/other. Splawski et al. (200) did not find it in 200 controls. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in 1000 Genomes ( as of November 6, 2014.

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