Submissions for variant NM_000218.3(KCNQ1):c.520C>T (p.Arg174Cys)

gnomAD frequency: 0.00001  dbSNP: rs199472696

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046072	SCV000074085	pathogenic	Long QT syndrome	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 174 of the KCNQ1 protein (p.Arg174Cys). 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: 9386136, 11668638, 15840476, 19716085, 23130128, 23392653). ClinVar contains an entry for this variant (Variation ID: 53058). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 19934648). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182078	SCV000234381	pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro functional studies demonstrate a damaging effect as the p.(R174C) variant impairs potassium channel regulation and function (Chouabe et al., 1997; Matavel et al., 2010; Wu et al., 2018); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 53058; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9312006, 23130128, 10973849, 15840476, 9386136, 26986070, 26907222, 29532034, 22581653, 19841300, 19716085, 19934648, 23392653, 27251404, 23728945, 26669661, 19815527, 27761162, 29037160, 29033053, 29449639, 11668638, 31737537, 32383558)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Color Diagnostics, LLC DBA Color Health	RCV001841647	SCV001350155	likely pathogenic	Cardiac arrhythmia	2018-11-04	criteria provided, single submitter	clinical testing	This missense variant is located in the cytoplasmic linker between transmembrane domains S2 and S3 of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that this variant adversely affects KCNQ1 channel function (PMID: 9312006, 19934648, 29449639). This variant has been reported in multiple unrelated individuals affected with long QT syndrome (PMID: 11668638, 23130128, 27251404, 29449639) and in individuals referred for long QT syndrome testing (PMID: 15840476, 19716085). This variant has also been reported in the homozygous and compound heterozygous state in individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 23392653, 29037160). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182078	SCV002103233	pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing	PP3, PM2_supporting, PM3, PS3, PS4_moderate
Ambry Genetics	RCV002345338	SCV002646655	pathogenic	Cardiovascular phenotype	2021-12-28	criteria provided, single submitter	clinical testing	The p.R174C pathogenic mutation (also known as c.520C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 520. The arginine at codon 174 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the S2/S3 transmembrane-spanning region. This variant has been reported in long QT syndrome (LQTS) cohorts and LQTS genetic testing cohorts, where some cases had limited details provided (Donger C et al. Circulation. 1997;96(9):2778-81; Splawski I et al. Circulation. 2000;102(10):1178-85; Tester DJ. Heart Rhythm. 2005;2(5):507-17; Couderc JP et al. J Am Heart Assoc. 2012;1:e000570; Miyazaki et al. JACC: Clin Electrophys. 2016;(2)3:266-76; Westphal DS et al. Mol Genet Genomic Med, 2020 09;8:e1300). This variant has also been reported in the homozygous and compound heterozygous states in patients with severe LQTS presentation and Jervell and Lange-Nielsen syndrome (Giudicessi JR et al. Circ Cardiovasc Genet. 2013;6(2):193-200; Uysal F et al. BMC Med Genet. 2017 10;18:114). This variant was also detected in two siblings with LQTS who had additional co-occurring variants in other arrhythmia-related genes; family members heterozygous for p.R174C with QTc values in the normal range were also described (Wu J et al. Sci Rep, 2018 02;8:3129). Functional studies have reported this alteration to disrupt regulation of ion channel activation and lead to impaired ion channel function (Chouabe C et al. EMBO J. 1997;16(17):5472-9; Matavel A et al. Channels (Austin). 2010;4(1):3-11; Huang H et al. Sci Adv, 2018 03;4:eaar2631). Furthermore, other variants affecting this amino acid (p.R174H, p.R174P, and p.R174L) have also been reported in LQTS cohorts (Lupoglazoff JM et al. J. Am Coll Cardiol. 2004;43(5):826-30; Napolitano C et al. JAMA. 2005; 294:2975-80; Aziz PF et al. Circ Arrhythm Electrophysiol. 2011;4:867-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002504938	SCV002816459	likely pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-10-11	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000587627	SCV003839125	pathogenic	Long QT syndrome 1	2022-11-27	criteria provided, single submitter	clinical testing	This KCNQ1 variant (rs199472696) is rare (<0.1%) in a large population dataset (gnomAD: 1/249462 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar5. This variant has been reported in the literature in multiple unrelated individuals affected with long QT syndrome. Alterations of the same codon have also been reported in individuals with LQT1. Experimental studies have shown that this amino acid substitution (p.Arg174Cys) adversely affects KCNQ1 channel function. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.520C>T to be pathogenic.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000587627	SCV004024200	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
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