Submissions for variant NM_000218.3(KCNQ1):c.583C>T (p.Arg195Trp)

gnomAD frequency: 0.00004  dbSNP: rs150172393

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148554	SCV000190267	uncertain significance	Long QT syndrome	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148554	SCV000254339	likely pathogenic	Long QT syndrome	2024-10-06	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 195 of the KCNQ1 protein (p.Arg195Trp). This variant is present in population databases (rs150172393, gnomAD 0.006%). This missense change has been observed in individuals with lone atrial fibrilliation and/or prolonged QT interval (PMID: 19716085, 25786344, 35703482; internal data). ClinVar contains an entry for this variant (Variation ID: 67087). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24947509, 25786344, 33600800). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001841687	SCV001346732	uncertain significance	Cardiac arrhythmia	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 195 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). A functional study has shown that this variant increases channel current while has no effect on the subcellular localization of the channel protein (PMID: 25786344). This variant has been reported in an individual affected with long QT syndrome (PMID: 35703482) and in two individuals referred for long QT syndrome testing (PMID: 19716085). It has also been reported in an individual affected with early-onset lone atrial fibrillation (PMID: 24144883, 25786344). This variant has been identified in 8/280548 chromosomes in the general population 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.
Fulgent Genetics, Fulgent Genetics	RCV002483094	SCV002783226	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162439	SCV003900425	uncertain significance	Cardiovascular phenotype	2023-03-02	criteria provided, single submitter	clinical testing	The p.R195W variant (also known as c.583C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 583. The arginine at codon 195 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a long QT syndrome clinical genetic testing cohort, an early-onset atrial fibrillation cohort, and an exome cohort, often with limited clinical detail (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Olesen MS et al. Heart Rhythm, 2014 Feb;11:246-51; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). In vitro studies have suggested that this mutant enhances the channel activity and reduces protein cell-surface expression; however, additional evidence is needed to confirm these findings. (Steffensen AB et al. J. Cardiovasc. Electrophysiol., 2015 Jul;26:715-23; Huang H et al. J Biol Chem. 2021 Feb;296:100423). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993784	SCV004813510	uncertain significance	not specified	2024-02-15	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.583C>T (p.Arg195Trp) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of 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 2.8e-05 in 249190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.583C>T has been reported in the literature in individuals affected with long-QT syndrome or atrial fibrillation (Kapplinger_2009, Olesen_2013, Steffensen_2015, Diebold_2020, Saat_2022). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least two publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Steffensen_2015, Huang_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 32048431, 33600800, 19716085, 24190995, 24144883, 35703482, 25786344). ClinVar contains an entry for this variant (Variation ID: 67087). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000148554	SCV004838762	uncertain significance	Long QT syndrome	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 195 of the KCNQ1 protein. This variant is found within the highly conserved cytoplasmic linker region (a.a. 169-196). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant increases channel current in Xenopus laevis oocytes (PMID: 25786344), while another study using a different expression system demonstrated that this variant causes reductions in cell surface expression, total expression, and trafficking efficiency compared to the wild type (PMID: 33600800). This variant has been reported in an individual affected with long QT syndrome (PMID: 35703482) and in two individuals referred for long QT syndrome testing (PMID: 19716085). It has also been reported in an individual affected with early-onset lone atrial fibrillation (PMID: 24144883, 25786344). This variant has been identified in 8/280548 chromosomes in the general population 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.
Lildballe Lab, Aarhus University Hospital	RCV004772836	SCV005200541	likely pathogenic	Atrial fibrillation	2024-03-01	criteria provided, single submitter	research	PM1(m), PP2(sup), PM2(sup), PP3(m)
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057713	SCV000089232	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.