rs199472696
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.520C>T(p.Arg174Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.520C>T | p.Arg174Cys | missense_variant | 3/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.520C>T | p.Arg174Cys | missense_variant | 3/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.139C>T | p.Arg47Cys | missense_variant | 3/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.259C>T | p.Arg87Cys | missense_variant | 4/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-12765C>T | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249462Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135368
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460282Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726530
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Nov 27, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes | Aug 01, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2021 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 02, 2021 | PP3, PM2_supporting, PM3, PS3, PS4_moderate - |
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Sep 10, 2015 | - - |
Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 11, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2021 | 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. - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 04, 2018 | 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. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at