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

gnomAD frequency: 0.00004  dbSNP: rs199473482

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182220	SCV000234523	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15851171, 16414944, 28749435, 34505893, 22581653, 24606995, 29021305)
Invitae	RCV000557272	SCV000627384	uncertain significance	Long QT syndrome	2022-07-09	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 individual(s) with clinical features of long QT syndrome (PMID: 15851171, 16414944, 24363352, 28749435). ClinVar contains an entry for this variant (Variation ID: 67053). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 28749435). 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.
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	2023-12-13	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
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.