Submissions for variant NM_000218.3(KCNQ1):c.1772G>A (p.Arg591His)

dbSNP: rs199472814

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505785	SCV000234528	pathogenic	not provided	2022-01-03	criteria provided, single submitter	clinical testing	Reported in multiple individuals in association with LQTS (Neyroud et al., 1999; Inoue et al., 2003; Shimizu et al., 2004; Grunnet et al., 2005; Tester et al., 2005; Moss et al,. 2007; Yasuda et al., 2008; Kapa et al., 2009; Kapplinger et al., 2009; Andrsova et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Cuneo et al., 2013; Robinson et al., 2015; Itoh et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as R591H causes a reduction in potassium ion current due to a reduction in the number of functional voltage-gated potassium channels in the cell membrane (Kanki et al., 2004; Grunnet et al., 2005; Xu et al., 2009); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53017; ClinVar); This variant is associated with the following publications: (PMID: 17470695, 15840476, 17329207, 22949429, 19716085, 19261104, 16253915, 12388934, 18174212, 19825999, 24713462, 19693805, 15140888, 26669661, 23995044, 10024302, 19841300, 15234419, 25916402, 23098067, 22727609, 12808265, 22885918, 17329209, 31395126, 32048431, 31737537)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678914	SCV000805118	pathogenic	Long QT syndrome 1	2017-11-14	criteria provided, single submitter	clinical testing
Invitae	RCV001388792	SCV001589930	pathogenic	Long QT syndrome	2023-12-05	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 591 of the KCNQ1 protein (p.Arg591His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10024302, 15234419, 16253915, 19261104, 21482651, 22727609, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53017). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 16253915, 20662986). This variant disrupts the p.Arg591 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22429796, 22949429, 23158531), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002399408	SCV002711855	pathogenic	Cardiovascular phenotype	2021-10-20	criteria provided, single submitter	clinical testing	The p.R591H pathogenic mutation (also known as c.1772G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1772. The arginine at codon 591 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with long QT syndrome (LQTS) and has also been reported in affected relatives (Neyroud N et al. Circ Res, 1999 Feb;84:290-7; Tester DJ et al. Heart Rhythm, 2006 Jul;3:815-21; Robinson JA et al. Congenit Heart Dis Apr;10:354-61; Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Functional studies have demonstrated defective protein trafficking and a significant reduction in potassium channel current (Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Horr S et al. J Cardiovasc Electrophysiol, 2011 Feb;22:193-200; David JP et al. Traffic, 2013 Apr;14:399-411). 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.
Dept of Medical Biology, Uskudar University	RCV001388792	SCV004022068	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS3_Moderate, PS4_Strong, PM1, PM2, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000505785	SCV004133917	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	KCNQ1: PM1:Strong, PM2, PM5, PS4:Moderate, PP1, PS3:Supporting
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV000678914	SCV005094554	pathogenic	Long QT syndrome 1	2024-07-19	criteria provided, single submitter	clinical testing	PS4_strong, PS3_supporting, PM1, PM2_supporting, PM5_supporting, PP3_moderate
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057636	SCV000089155	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:10024302;PMID:15840476;PMID:16253915;PMID:16818214;PMID:17329209;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695;PMID:17329207;PMID:9386136). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.