Submissions for variant NM_000218.3(KCNQ1):c.940G>A (p.Gly314Ser)

dbSNP: rs120074184

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182137	SCV000234440	pathogenic	not provided	2024-03-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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 it failed to produce functional homomeric channels, and reduced the K+ current when co-expressed with the wild-type subunit (PMID: 30571187, 9312006); This variant is associated with the following publications: (PMID: 10973849, 25554238, 9799083, 34505893, 34860437, 32048431, 22949429, 9312006, 9693036, 15234419, 15840476, 16038262, 17470695, 19348785, 19716085, 27041150, 27251404, 27041096, 15051636, 9386136, 8872472, 10220144, 12566525, 15028050, 16922724, 19841300, 22581653, 31737537, 32797034, 31493592, 30571187)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000003271	SCV000805122	pathogenic	Long QT syndrome 1	2017-11-20	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852434	SCV000995119	pathogenic	Long QT syndrome	2018-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000852434	SCV001592372	pathogenic	Long QT syndrome	2022-12-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 15051636, 19348785). 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. ClinVar contains an entry for this variant (Variation ID: 3123). This variant is also known as G185S. This missense change has been observed in individuals with long QT syndrome (PMID: 8872472, 9799083, 16922724, 22727609, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 314 of the KCNQ1 protein (p.Gly314Ser).
Ambry Genetics	RCV002371756	SCV002686454	pathogenic	Cardiovascular phenotype	2018-06-08	criteria provided, single submitter	clinical testing	The p.G314S pathogenic mutation (also known as c.940G>A), located in coding exon 7 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 940. The glycine at codon 314 is replaced by serine, an amino acid with similar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGD) located between transmembrane helices S5 and S6. This variant has been identified in multiple patients with long QT syndrome (LQTS) and was reported to co-segregate with disease in several families (Russell MW et al. Hum. Mol. Genet. 1996;5:1319-24; Donger C et al. Circulation. 1997;96:2778-81; Kobori A et al. J. Cardiovasc. Electrophysiol. 2004;15:190-9; Kapa S et al. Circulation. 2009;120:1752-60; Hofman N et al. Neth Heart J. 2011;19:10-16). Functional studies suggest this mutation causes significantly reduced current density in heterologous expression studies (Chouabe C et al. EMBO J. 1997;16:5472-9; Westenskow P et al. Circulation. 2004;109:1834-41). In addition, internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Dept of Medical Biology, Uskudar University	RCV000852434	SCV004022044	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS2_Moderate, PS3_Moderate, PM1, PM2, PP1_Strong, PP3
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000003271	SCV004024199	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000003271	SCV004239020	pathogenic	Long QT syndrome 1	2024-01-03	criteria provided, single submitter	clinical testing
OMIM	RCV000003271	SCV000023429	pathogenic	Long QT syndrome 1	1996-09-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057810	SCV000089330	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:8872472;PMID:9386136;PMID:9693036;PMID:9799083;PMID:10220144;PMID:12566525;PMID:15028050;PMID:15051636;PMID:15840476;PMID:16038262;PMID:16922724;PMID:19348785;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.