Submissions for variant NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)

dbSNP: rs199473411

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045959	SCV000073972	pathogenic	Long QT syndrome	2023-12-23	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 366 of the KCNQ1 protein (p.Arg366Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9693036, 15466642, 19716085, 19841300, 22949429, 24357532). ClinVar contains an entry for this variant (Variation ID: 52955). 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: 16556865). This variant disrupts the p.Arg366 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9024139, 10973849, 16556865, 19934648). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182173	SCV000234476	pathogenic	not provided	2022-01-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that R366W impairs calmodulin binding and disrupts channel expression and function (Shamgar et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#52955; ClinVar); This variant is associated with the following publications: (PMID: 24357532, 26063740, 27231019, 9693036, 22949429, 16556865, 25525159, 15466642, 19716085, 10220146, 14678125, 12388934, 24606995, 26669661, 31737537, 31447099, 29790872, 29740400, 30508507, 34135346, 34691145, 29497013)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000496023	SCV000584099	pathogenic	Long QT syndrome 1	2015-02-10	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057551	SCV000731642	likely pathogenic	Congenital long QT syndrome	2017-07-24	criteria provided, single submitter	clinical testing	The p.Arg366Trp variant in KCNQ1 has been reported in >12 individuals with long QT syndrome (Splawski 1998, Choi 2004, Kapplinger 2009, Kapa 2009, Giudicessi 20 12, and Torekov 2014) and has also been reported by other clinical laboratories in ClinVar (Variation ID 52955). This variant was absent from large population s tudies. In vitro functional studies provide some evidence that the p.Arg366Trp v ariant may impact protein function (Shamgar 2006). Computational prediction tool s and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg366Trp variant meets criteria to be likely pathogenic for autosomal dominant long QT syndrome. ACMG/AMP Criteria applied: PM2, PS4_Mo derate, PS3_Supporting, PP3.
Ambry Genetics	RCV000617196	SCV000737621	pathogenic	Cardiovascular phenotype	2021-01-29	criteria provided, single submitter	clinical testing	The p.R366W pathogenic mutation (also known as c.1096C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1096. The arginine at codon 366 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in unrelated individuals reported to have long QT syndrome (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Choi G et al. Circulation. 2004;110(15):2119-24; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Giudicessi JR. et al. Circ Cardiovasc Genet. 2012;5(5):519-28; Torekov SS et al. Diabetes. 2014;63(4):1315-25). One in vitro study reported this alteration to result in impaired binding to calmodulin, altered ion channel kinetics, and reduced cell surface expression (Shamgar L et al. Circ Res. 2006;98(8):1055-63). In addition, other alterations affecting the same amino acid (p.R366P (c.1097G>C) and p.R366Q (c.1097G>A)) have also been reported in association with LQTS (Splawski I et al. Circulation. 2000;102(10):1178-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000496023	SCV001422302	pathogenic	Long QT syndrome 1	2020-01-16	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000496023	SCV001433411	pathogenic	Long QT syndrome 1	2020-02-25	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000496023	SCV004024196	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000496023	SCV004100810	likely pathogenic	Long QT syndrome 1	2023-10-12	criteria provided, single submitter	clinical testing	We observed a heterozygous c.1096C>T (p.Arg366Trp) genetic variant in the KCNQ1 gene on WES data in a 7-month-old male proband diagnosed with long QT syndrome. ClinVar contains an entry for this variant (Variation ID: 52955) observed in patients with the consistent phenotype. This variant is not present in gnomAD database and located in a mutational hot spot and/or critical and well-established functional domain (PM1_strong according to Walsh R. et al. (PMID: 32893267). Multiple computational resources predict deleterious effect of p.Arg366Trp genetic variant. Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that p.Arg366Trp impairs calmodulin binding and disrupts channel expression and function (PMID: 16556865). For these reasons, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057551	SCV000089070	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:9693036;PMID:10220146;PMID:11668638;PMID:14678125;PMID:15466642;PMID:15840476;PMID:16937190;PMID:19716085;PMID:19841300;PMID:10090529). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000496023	SCV000863813	pathogenic	Long QT syndrome 1	2018-02-19	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000182173	SCV001926681	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182173	SCV001958223	pathogenic	not provided		no assertion criteria provided	clinical testing