Submissions for variant NM_000218.3(KCNQ1):c.521G>A (p.Arg174His)

gnomAD frequency: 0.00001  dbSNP: rs199472697

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	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	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 174 of the KCNQ1 protein (p.Arg174His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 14998624, 19716085, 23130128; Invitae). ClinVar contains an entry for this variant (Variation ID: 53059). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187). This variant disrupts the p.Arg174 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 15840476, 23130128, 23392653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002336182	SCV002642027	likely pathogenic	Cardiovascular phenotype	2023-11-16	criteria provided, single submitter	clinical testing	The p.R174H variant (also known as c.521G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 521. The arginine at codon 174 is replaced by histidine, an amino acid with highly similar properties. This variant has been described in association with long QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004;43(5):826-30; Shimizu W et al. J. Am. Coll. Cardiol. 2004;44(1):117-25; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). Functional analysis suggests this alteration causes a dominant negative trafficking defect (Vanoye CG et al. Circ Genom Precis Med, 2018 11;11:e002345; Huang H et al. Sci Adv. 2018;4:eaar2631). 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.
Fulgent Genetics, Fulgent Genetics	RCV002496703	SCV002796331	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-12-03	criteria provided, single submitter	clinical testing
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 cardiodb.org, 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 (http://genetics.bwh.harvard.edu/pph2/) 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 (http://evs.gs.washington.edu/EVS/), 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 (http://browser.1000genomes.org/index.htm) as of November 6, 2014.