ClinVar Genomic variation as it relates to human health

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 322 of the KCNQ1 protein (p.Thr322Met). This variant is present in population databases (rs199472755, gnomAD 0.0009%). This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 16414944, 17470695, 18400097, 19716085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53151). 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: 23092362). For these reasons, this variant has been classified as Pathogenic.

Identified in multiple unrelated patients with LQTS either referred for genetic testing at GeneDx or in published literature (Napolitano et al., 2005; Zhang et al., 2008; Kapplinger et al., 2009; Jons et al., 2009; Barsheshet et al., 2012; Burgess et al., 2012; Toyota et al., 2015; Shigemizu et al., 2105; Itoh et al., 2016; Wang et al., 2017; Kwok et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Published functional studies demonstrate that T322M generates non-functional channels and causes dominant negative current suppression (Burgess et al., 2012; Mousavi et al., 2015; Rothenberg et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic (ClinVar Variant ID# 53151; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22629021, 26743238, 18400097, 16414944, 23092362, 17470695, 19716085, 22456477, 19490272, 26344792, 26132555, 25705178, 26669661, 22956155, 28491751, 25028166, 27917693, 30530868)

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.

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.