Submissions for variant NM_000218.3(KCNQ1):c.1748G>A (p.Arg583His)

gnomAD frequency: 0.00004  dbSNP: rs199473482

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182220	SCV000234523	likely pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15851171, 16414944, 28749435, 34505893, 22581653, 29021305, 24606995)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557272	SCV000627384	likely pathogenic	Long QT syndrome	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 583 of the KCNQ1 protein (p.Arg583His). This variant is present in population databases (rs199473482, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 15851171, 16414944, 24363352, 28749435, 34505893, 38657442; internal data). ClinVar contains an entry for this variant (Variation ID: 67053). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 28749435, 38657442). This variant disrupts the p.Arg583 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV001841675	SCV001349235	uncertain significance	Cardiac arrhythmia	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 583 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 does not cause severe functional impairment in transfected cells (PMID: 28749435). This variant has been reported in at least 4 unrelated individuals affected with long QT syndrome (15851171, 16414944, 18822425, 22456477, 24363352, 2460699, 26318259, 28749435, 32893267), in an individual affected with sudden unexpected death and epilepsy (PMID: 26423924), and in an individual suspected of having epilepsy (PMID: 31696929). This variant has been identified in 5/282380 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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV002054904	SCV002320709	likely pathogenic	Long QT syndrome 1	2021-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298107	SCV003997455	uncertain significance	Cardiovascular phenotype	2023-04-04	criteria provided, single submitter	clinical testing	The p.R583H variant (also known as c.1748G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1748. The arginine at codon 583 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in an individual with arrhythmia, a sudden unexplained death in epilepsy cohort, and long QT syndrome cohorts; however, in some cases, clinical detail was limited and additional variants in other arrhythmia-related genes were also detected. In addition, some reported cases may overlap (Kanters JK et al. Heart Rhythm, 2004 Sep;1:285-92; Christiansen M et al. BMC Med Genet, 2014 Mar;15:31; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Barsheshet A et al. Circulation, 2012 Apr;125:1988-96; Yoshinaga M et al. Circ Arrhythm Electrophysiol, 2014 Feb;7:107-12; Coll M et al. Int J Legal Med, 2016 Mar;130:331-9; Zullo A et al. Int J Mol Sci, 2017 Jul;18; Schwartz PJ et al. Eur Heart J, 2021 Dec;42:4743-4755). One functional study indicated this variant may impact some channel electrophysiological parameters, but not significantly impact current density; however, additional evidence is needed to confirm these findings (Zullo A et al. Int J Mol Sci, 2017 Jul;18). 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 limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000557272	SCV004836477	uncertain significance	Long QT syndrome	2024-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 583 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 does not cause severe functional impairment in transfected cells (PMID: 28749435). This variant has been reported in at least 4 unrelated individuals affected with long QT syndrome (15851171, 16414944, 18822425, 22456477, 24363352, 2460699, 26318259, 28749435, 32893267), in an individual affected with sudden unexpected death and epilepsy (PMID: 26423924), and in an individual suspected of having epilepsy (PMID: 31696929). This variant has been identified in 5/282380 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.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV002054904	SCV005050139	likely pathogenic	Long QT syndrome 1	2024-05-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841675	SCV005380685	likely pathogenic	Cardiac arrhythmia	2024-08-29	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1748G>A (p.Arg583His) results in a non-conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251018 control chromosomes. c.1748G>A has been reported in the literature in multiple individuals affected with Arrhythmia and in two families, this variant has been shown to segregate with disease (Kanters_2004, Li_2024). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function. While one experiment study shows that the variant results in impeded channel protein activation in the whole-cell patch-clamp assay and >70% reduction of forskolin-induced channel current (Li_2024), the other failed to find a signicifant effect of this variant on channel activity (Zullo_2017). The following publications have been ascertained in the context of this evaluation (PMID: 15851171, 38657442, 16414944, 34505893, 28749435). ClinVar contains an entry for this variant (Variation ID: 67053). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002054904	SCV005398146	uncertain significance	Long QT syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated C-terminal domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously identified in four individuals with LQTS and in one individual who suffered a sudden unexpected death in epilepsy (PMID: 16414944, PMID: 24606995, PMID: 24363352, PMID: 26423924, PMID: 28749435). This variant also has three VUS entries in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Whole cell patch clamp analysis demonstrated the variant caused a positive shift in the voltage-dependence of activation but does not severely affect the function of the channel (PMID: 28749435). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000182220	SCV005894576	likely pathogenic	not provided	2025-02-01	criteria provided, single submitter	clinical testing	KCNQ1: PP1:Strong, PM1, PS4:Moderate
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057629	SCV000089148	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:15851171;PMID:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.