ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp) (rs199473411)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045959 SCV000073972 pathogenic Long QT syndrome 2020-02-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 366 of the KCNQ1 protein (p.Arg366Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 9693036, 15466642, 19716085, 19841300, 22949429, 24357532). ClinVar contains an entry for this variant (Variation ID: 52955). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. Experimental studies have shown that this missense change impairs calmodulin binding and alters channel gating by generating a voltage-dependent slow inactivation (PMID: 16556865). Two additional missense substitutions at this codon (p.Arg366Pro, p.Arg366Gln) are reported to be deleterious (PMID: 9024139, 10973849, 16556865, 19934648). This indicates that the p.Arg366 residue is important for KCNQ1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182173 SCV000234476 pathogenic not provided 2021-04-15 criteria provided, single submitter clinical testing Reported in multiple individuals in association with LQTS (Splawski et al., 1998; Larsen et al., 1999; Zareba et al., 2003; Choi et al., 2004; Kapplinger et al., 2009; Christiansen et al., 2014; Itoh et al., 2016; Mak et al., 2018; Huttunen et al., 2018; Marschall et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#52955; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24357532, 26063740, 27231019, 9693036, 22949429, 16556865, 25525159, 15466642, 19716085, 10220146, 14678125, 12388934, 24606995, 26669661, 29497013, 31737537, 31447099, 29790872, 29740400, 30508507)
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, Partners HealthCare 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 likely pathogenic Cardiovascular phenotype 2017-02-28 criteria provided, single submitter clinical testing The p.R366W variant (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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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
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
Human Genetics - Radboudumc,Radboudumc RCV000182173 SCV001958223 pathogenic not provided no assertion criteria provided clinical testing

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