Submissions for variant NM_000218.3(KCNQ1):c.1700T>C (p.Ile567Thr)

dbSNP: rs199472805

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046016	SCV000074029	pathogenic	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 567 of the KCNQ1 protein (p.Ile567Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (LQTs) and/or Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 16414944, 19716085, 22429796, 23130128, 24372464). ClinVar contains an entry for this variant (Variation ID: 53007). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. This variant disrupts the p.Ile567 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17470695, 22456477). 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.
GeneDx	RCV000182217	SCV000234520	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Reported in association with Long QT syndrome (Napolitano et al., 2005; Kapplinger et al., 2009; Obeyesekere et al., 2012; Crotti et al., 2012; Couderc et al., 2012; Izumi et al., 2016; Wong et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27041096, 23130128, 25981146, 24372464, 22429796, 16414944, 28438721, 23158531, 31424047, 19716085)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000046016	SCV000987403	likely pathogenic	Long QT syndrome		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841636	SCV001352302	likely pathogenic	Cardiac arrhythmia	2019-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 567 in the cytoplasmic C-terminal region of the KCNQ1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 16414944, 22429796, 23130128, 29925740, 31424047) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been reported in the homozygous state in individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 24372464). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001258363	SCV001435332	likely pathogenic	Long QT syndrome 1	2020-09-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399407	SCV002714151	pathogenic	Cardiovascular phenotype	2023-01-18	criteria provided, single submitter	clinical testing	The p.I567T pathogenic mutation (also known as c.1700T>C), located in coding exon 14 of the KCNQ1 gene, results from a T to C substitution at nucleotide position 1700. The isoleucine at codon 567 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in association with long QT syndrome (LQTS) (Napolitano C, JAMA 2005 Dec; 294(23):2975-80; Kapplinger JD, Heart Rhythm 2009 Sep; 6(9):1297-303; Obeyesekere MN, J. Cardiovasc. Electrophysiol. 2012 Jun; 23(6):637-42; Wong AR et al. Med J Malaysia, 2019 Aug;74:341-343; Yee LA et al. J Am Heart Assoc, 2022 Sep;11:e025108). This alteration has also been reported as homozygous in subjects with deafness and prolonged QT (Al-Aama JY et al. Clin. Genet., 2015 Dec;87:74-9; Al-Hassnan ZN et al. Heart Rhythm, 2017 Aug;14:1191-1199). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057620	SCV000089139	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:16414944;PMID:19716085;PMID:22429796). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.