ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.584C>T (p.Thr195Met) (rs199472755)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000190213 SCV000074196 pathogenic Long QT syndrome 2020-08-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 322 of the KCNQ1 protein (p.Thr322Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This sequence change has been reported in the literature and is not currently found in any individuals from the population databases (rs199472755, no frequency). This sequence change has been reported in at least five unrelated patients with long QT syndrome (PMID: 16414944, 17470695, 19716085). In addition, the p.Thr322Met sequence change was observed in the homozygous state in two Jervell-Lange Nielsen patients in a family in PMID: 18400097. Heterozgous carriers of this sequence change in this family had a range of phenotypes; two were phenotypically normal, one had a borderline QT interval, and two carriers were diagnosed with classic long QT syndrome. Experimental studies have shown that heterologous expression of this missense change along with KCNE1 generates non-functional channels and causes dominant negative suppression of current in vitro (PMID: 23092362). This sequence change is currently listed in ClinVar as Pathogenic (RCV000057831, Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust); however, the evidence supporting this interpretation has not been provided. This sequence change is not reported in population databases, has been observed in multuple individuals with long QT and has been shown to cause Jervell-Lange Nielsen syndrome in the homozygous state, and there is functional evidence demonstrating that the p.Thr322Met missense change is deleterious. For these reasons, this sequence change has been classified as Pathogenic.
GeneDx RCV000182149 SCV000234452 pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing The T322M pathogenic variant in the KCNQ1 gene has been reported in in multiple individuals with LQTS (Napolitano et al., 2005; Zhang et al., 2008; Kapplinger et al., 2009; Jons et al., 2009; Barsheshet et al., 2012; Toyota et al., 2015; Shigemizu et al., 2105; Itoh et al., 2016; Wang et al., 2017). The T322M variant has also been observed in the homozygous state in two siblings with JLNS, as well as in the heterozygous state in two family members with LQT1 (Zhang et al., 2009). Additionally, the T322M variant was observed in another individual with JLNS who harbored another KCNQ1 variant in trans, and was also observed in that individuals mother who had a borderline prolonged QTc interval (Wang et al., 2017). Furthermore, the T322M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). T322M results in a non-conservative/semi-conservative amino acid substitution and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies demonstrated that T322M generates nonfunctional channels and causes dominant negative current suppression (Burgess et al., 2012; Mousavi et al., 2015; Rothenberg et al., 2016). A pathogenic variant in the same residue (T322A) and likely pathogenic and pathogenic variants in nearby residues (D317N, P320S, G325R, G325E) have been reported at GeneDx in association with LQTS, further supporting the functional importance of this residue and region of the protein.
Ambry Genetics RCV000247480 SCV000320507 pathogenic Cardiovascular phenotype 2018-08-16 criteria provided, single submitter clinical testing The p.T322M pathogenic mutation (also known as c.965C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 965. The threonine at codon 322 is replaced by methionine, an amino acid with some similar properties, and is located in the pore/S6 transmembrane spanning region. This alteration has been reported in multiple unrelated individuals with known or suspected long QT syndrome (LQTS) (Napolitano C et al. JAMA. 2005;294(23):2975-80; Moss AJ et al. Circulation. 2007;115(19):2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Aziz PF et al. Circ Arrhythm Electrophysiol. 2011;4(6):867-73; Clur SB et al. Circ Arrhythm Electrophysiol. 2018;11(4):e005797). One study reported this alteration in multiple individuals in several families with LQTS (Burgess DE et al. Biochemistry. 2012;51(45):9076-85). This alteration has been reported in the homozygous state in two siblings with Jervell and Lange-Nielsen syndrome, and in the heterozygous state in two relatives reported to have prolonged QT intervals (Zhang S et al. BMC Med Genet. 2008;9:24). This alteration was also reported to co-occur with a KCNQ1 frame shift alteration in a patient with LQTS and syncope starting at three years of age (Toyota N et al. Heart Vessels. 2015 Sep; 30(5):687-91). In addition, in vitro studies suggest this alteration to result in abnormal protein function and trafficking (Burgess DE et al. Biochemistry. 2012;51(45):9076-85; Mousavi Nik A et al. Front Cell Neurosci. 2015;9:32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057831 SCV000089351 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:16414944;PMID:18400097;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Medical Research Institute,Tokyo Medical and Dental University RCV000190213 SCV000222064 likely pathogenic Long QT syndrome no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.