Submissions for variant NM_000218.3(KCNQ1):c.1189C>T (p.Arg397Trp)

gnomAD frequency: 0.00013  dbSNP: rs199472776

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182181	SCV000234484	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	Reported in association with LQTS or sudden death and in individuals referred for LQTS genetic testing; however, the majority of these publications did not provide specific clinical details or familial segregation data (PMID: 17470695, 19841300, 19716085, 23571586, 24440382, 34505893); Identified in a patient with CPVT in published literature (PMID: 32553227); 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: 29197658, 25637381, 25985138, 19716085, 22378279, 22949429, 19841300, 23571586, 26159999, 24440382, 32048431, 32233023, 31737537, 30615648, 31019283, 28988457, 34426522, 34398675, 35008927, 34505893, 34621001, RidaM2023[Preprint], 35534676, 24190995, 22199116, 22581653, 32553227, 17470695)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203070	SCV000257644	likely pathogenic	Long QT syndrome 1	2015-03-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000148545	SCV000370280	likely pathogenic	Long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing	The c.1189C>T (p.Arg397Trp) variant has been identified in a heterozygous state in at least seven patients with clinically-diagnosed long QT syndrome, in a heterozygous state in three individuals with an unclear clinical diagnosis, and in a heterozygous state in two unaffected individuals (Moss et al. 2007; Kapa et al. 2009; Kapplinger et al. 2009; Amin et al. 2012; Ghouse et al. 2015). The p.Arg397Trp variant was absent from 2300 controls but is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. Functional studies of electrophysiological properties in HEK293 cells and Xenopus oocytes demonstrated that the p.Arg397Trp variant reduced the hIK currents and ATP sensitivity of the channel (Crotti et al. 2013; Li et al. 2013). Based on the evidence, the p.Arg397Trp variant is classified as likely pathogenic for long QT syndrome.
Illumina Laboratory Services, Illumina	RCV000265217	SCV000370281	uncertain significance	Jervell and Lange-Nielsen syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000356516	SCV000370283	uncertain significance	Familial atrial fibrillation	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000057571	SCV000370284	uncertain significance	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619428	SCV000735521	uncertain significance	Cardiovascular phenotype	2024-03-12	criteria provided, single submitter	clinical testing	The p.R397W variant (also known as c.1189C>T), located in coding exon 9 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1189. The arginine at codon 397 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been previously reported in individuals with suspicion of long QT syndrome or unexplained fetal death (Moss AJ et al. Circulation. 2007;115(19):2481-9; Kapa S et al. Circulation. 2009;120(18):1752-60; Crotti L et al. JAMA. 2013;309(14):1473-82; Sahlin E et al. PLoS ONE, 2019 Jan;14:e0210017). In vitro functional studies have reported this alteration to result in altered ion channel function, but these experiments may not accurately reflect physiological conditions in vivo (Crotti L et al. JAMA. 2013;309(14):1473-82; Li Y et al. Proc Natl Acad Sci U.S.A. 2013;110(47):18922-7). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000203070	SCV000883083	likely pathogenic	Long QT syndrome 1	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841626	SCV000913883	uncertain significance	Cardiac arrhythmia	2024-01-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 397 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may result in reduced potassium ionic current (PMID: 23571586) and reduced ATP sensitivity (PMID: 24190995). This variant has been reported in individuals with a family history of long QT syndrome (PMID: 17470695), in one individual with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227), in individuals with sudden death (PMID: 23571586, 24440382), and in a stillbirth case (PMID: 30615648). This variant has also been identified in individuals with normal QTc intervals (PMID: 26159999) and showed no significant association with prolonged QTc interval in the Icelandic population (PMID: 37449562). This variant occurs at an appreciable frequency in the general population and has been identified in 53/282726 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825350	SCV000966645	uncertain significance	not specified	2019-01-29	criteria provided, single submitter	clinical testing	The p.Arg397Trp variant in KCNQ1 has been reported in 9 individuals with LQTS (Moss 2007, Kapplinger 2009, Giudicessi 2012, Amin 2012). However, it has also been detected in asymptomatic individuals (Ghouse 2015, Taylor 2015) and in 0.03% (39/129098) of European chromosomes and 0.09% (9/10364) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 52970). In vitro functional studies provide some evidence that the p.Arg397Trp variant may impact protein function (Li 2013); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis support an impact to the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to the presence of conflicting evidence, the clinical significance of the p.Arg397Trp variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting, PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000182181	SCV001148157	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	KCNQ1: PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148545	SCV001487505	uncertain significance	Long QT syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 397 of the KCNQ1 protein (p.Arg397Trp). This variant is present in population databases (rs199472776, gnomAD 0.08%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 17470695, 19841300). ClinVar contains an entry for this variant (Variation ID: 52970). 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: 23571586, 24190995). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
New York Genome Center	RCV002467560	SCV002764487	uncertain significance	Atrial fibrillation, familial, 3; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2020-06-19	criteria provided, single submitter	clinical testing	The c.1189C>T (p.Arg397Trp) variant identified in the KCNQ1 gene substitutes a well conserved Arginine for Tryptophan at amino acid 397/677 (exon 9/16), and is also referred to asp.Arg270Trp annotated from transcript NM_181798.1. This variant is reported in gnomAD with an allele frequency of 1.26e-4 (v3.0; 18 heterozygotes, 0 homozygotes)and 1.88e-4 (v2.1.1; 53 heterozygotes, 0 homozygotes). In silico algorithms predict this variant to be Deleterious (SIFT; score: 0.001), Damaging (Provean; score: -3.32),and Pathogenic (REVEL; score: 0.7599) to the function of the canonical transcript. The p.Arg397 residue is in the intracellular C-terminal domain of KCNQ1 (UniProtKB:P51787). This variant has been reported many times in ClinVar with varying interpretations including Likely Pathogenic, Benign, and a Variant of Uncertain Significance (VarID:52970). The c.1189C>T (p.Arg397Trp) variant identified here has been reported in several affected individuals in the literature [PMID:17470695;PMID:19841300;PMID:22199116;PMID:22456477;PMID:24440382], however many of these studies were panel based and examined only a small number of potentially causative genes. Functional studies suggest the p.Arg397Trp variant leads to reduced current densities [PMID:23571586;PMID:24190995], and may be involved in coordination of ATP binding [PMID:24190995]. While it has been observed in several affected individuals and in vitro functional studies suggest an effect on current density, the presence of this variant at an allele frequency higher than expected in control databases leave some uncertainty regarding its pathogenicity. Given that, the c.1189C>T (p.Arg397Trp) variant identified in the KCNQ1 gene is reported as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825350	SCV003934365	uncertain significance	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251342 control chromosomes, predominantly at a frequency of 0.00032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Long QT Syndrome phenotype (8.3e-05). c.1189C>T has been reported in the literature in many individuals affected with Long QT Syndrome (e.g., Moss_2007, Kapa_2009, Kapplinger_2009, Amin_2012) as well as an in an intrauterine fetal death (e.g., Crotti_2013) and a sillbirth case (e.g., Sahlin_2019). However, co-segregation data was not provided to confirm causality in these cases and in some cases, co-occurring variants of uncertain significance were reported. Therefore, these data do not allow any conclusion about variant significance. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant reduced the slowly activating K+ channel current densities by >70% compared to wild type and reduced ATP sensitivity as well (e.g., Li_2013, Crotti_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22199116, 23571586, 19841300, 25854863, 24190995, 17470695, 30615648). ClinVar contains an entry for this variant (Variation ID: 52970). Based on the evidence outlined above, the variant was classified as uncertain significance.
Dept of Medical Biology, Uskudar University	RCV000148545	SCV004022050	likely pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS4_Strong, PS3_Supporting, PP3
Molecular Genetics, Royal Melbourne Hospital	RCV000203070	SCV004812468	uncertain significance	Long QT syndrome 1	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change in KCNQ1 is predicted to replace arginine with tryptophan at codon 397, p.(Arg397Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (39/129,098 alleles) in the European non-Finnish population. This variant has been reported in multiple probands with KCNQ1-related cardiac arrhythmias (PMID: 19841300, 31737537). An in vitro functional assay using HEK293T cells showed a decrease in current density indicating that this variant impacts protein function (PMID: 23571586). Another functional study using a patch clamp assay in Xenopus oocytes showed a partial loss of conduction in the presence of this mutant and a complete loss of conduction in combination with another mutant suggestive that this variant impacts protein function (PMID: 24190995). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.76). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3, PS3_Supporting
All of Us Research Program, National Institutes of Health	RCV000148545	SCV004836393	uncertain significance	Long QT syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 397 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may result in reduced potassium ionic current (PMID: 23571586) and reduced ATP sensitivity (PMID: 24190995). This variant has been reported in individuals with a family history of long QT syndrome (PMID: 17470695), in one individual with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227), in individuals with sudden death (PMID: 23571586, 24440382), and in a stillbirth case (PMID: 30615648). This variant has also been identified in individuals with normal QTc intervals (PMID: 26159999) and showed no significant association with prolonged QTc interval in the Icelandic population (PMID: 37449562). This variant occurs at an appreciable frequency in the general population and has been identified in 53/282726 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057571	SCV000089090	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:17470695;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148545	SCV000190258	likely benign	Long QT syndrome	2014-06-01	flagged submission	research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656189	SCV000678383	likely pathogenic	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome