ClinVar Genomic variation as it relates to human health

Variant summary: The c.1838C>T (p.Thr613Met) in KCNH2 gene is a missense change that alters a highly conserved nucleotide and 5/5 in silico tools predict neutral outcome. The variant located in the pore region and several alterations of neighboring codons have been identified in LQTS pts. The variant was not observed in the large cohort of the ExAC project. The variant has been reported in multiple affected individuals with confirmed dx of LQTS and has it been cited as Likely Pathogenic/Pathogenic by several reputable databases/clinical laboratories. Taking together, the variant of interest was classified as Pathogenic.

The KCNH2 c.1838C>T; p.Thr613Met variant (rs199473524) is reported in the literature in multiple individuals affected with long QT syndrome (Amirian 2018, Jongbloed 1999, Komiya 2004, Laitinen 2000, Miyake 2016, Simpson 2009). The variant was absent from the parents of at least three affected individuals, suggesting a de novo origin, with paternity and maternity demonstrated in at least one case (Amirian 2018, Laitinen 2000, Simpson 2009). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 613 is highly conserved, it occurs in functionally important pore helix domain, and functional studies suggest the variant protein is not properly trafficked to the cell membrane (Anderson 2014). Other missense variants within the pore helix domain (p.Tyr611His, p.Val612Leu, p.Ala614Val) have also been reported in individuals with long QT syndrome and are improperly trafficked in the cell (Anderson 2014, Jongbloed 1999). Based on available information, the p.Thr613Met variant is considered to be pathogenic. References: Amirian A et al. Molecular Analysis of KCNQ1, KCNH2 and SCN5A Genes in Iranian Patients with Long QT Syndrome. J Mol Genet Med 2018, 12:3. Anderson CL et al. Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. Nat Commun. 2014 Nov 24;5:5535. Jongbloed RJ et al. Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Hum Mutat. 1999;13(4):301-10. Komiya N et al. A patient with LQTS in whom verapamil administration and permanent pacemaker implantation were useful for preventing torsade de pointes. Pacing Clin Electrophysiol. 2004 Jan;27(1):123-4. Laitinen P et al. Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects. Hum Mutat. 2000 Jun;15(6):580-1. Miyake A et al. Successful prenatal management of ventricular tachycardia and second-degree atrioventricular block in fetal long QT syndrome. HeartRhythm Case Rep. 2016 Sep 21;3(1):53-57. Simpson JM et al. Fetal ventricular tachycardia secondary to long QT syndrome treated with maternal intravenous magnesium: case report and review of the literature. Ultrasound Obstet Gynecol. 2009 Oct;34(4):475-80.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Functional studies show that T613M results in deficient protein trafficking (Anderson et al., 2014; Ng et al., 2019); Reported in ClinVar (ClinVar Variant ID# 67292; ClinVar); This variant is associated with the following publications: (PMID: 10862094, 22402334, 10220144, 19731233, 22949429, 14720170, 14998624, 15466642, 28491768, 30036649, 34319147, 33731522, 31557540, 33665105, 25417810)

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP1,PP3.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 613 of the KCNH2 protein (p.Thr613Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10220144, 10862094, 10973849, 14720170, 14998624, 18441445, 19731233, 22402334, 22949429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 67292). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 11524404, 25417810). For these reasons, this variant has been classified as Pathogenic.

The p.T613M pathogenic mutation (also known as c.1838C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1838. The threonine at codon 613 is replaced by methionine, an amino acid with similar properties. This alteration has been described in multiple neonatal, pediatric, and adult cases of long QT syndrome (LQTS) type 2 and sudden death (Jongbloed RJ et al. Hum. Mutat. 1999;13(4):301-10, Lupoglazoff JM et al. J Am Coll Cardiol. 2004;43(5):826-30; Miller TE et al. Genet Med. 2007;9(1):23-33; Nagaoka I et al. Circ J. 2008;72(5):694-9; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5(5):519-28). In two different studies of LQTS clinical genetic testing, this alteration was reported in six patients from one cohort followed by seven patients from the other cohort (Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This alteration is located in the pore helix region, participating in voltage-related inactivation of KCNH2 channels, and functional in vitro studies have demonstrated deficient protein trafficking and suppression of channel function due to severe dominant-negative effects of this alteration (Huang FD et al. Circulation. 2001;104(9):1071-5; Anderson CL et al. Nat Commun. 2014 Nov 24;5:5535). Another alteration in the same codon (p.T613A c.1837A>G) has been described to co-segregate with LQTS in a sibling and the father of an individual who died suddenly after exercise (Poulsen KL et al. Pacing Clin Electrophysiol. 2015 Jul 14;doi:10.1111/pace.12693), and in the same study, functional in vitro analysis demonstrated the alteration reduced cardiac channel expression related to a loss of function effect. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Thr613Met Based on the evidence provided below, we too consider this variant likely disease causing. This variant has been reported in at least 12 unrelated subjects with LQTS in the scientific literature and in arrhythmia databases as of October 2013. Some weak segregation data is presented in two of these studies and another group presented some functional data in support of a dominant negative effect of this mutation. This is a non-conservative amino acid substitution in which a polar threonine is replaced by a nonpolar methionine. In silico analysis with Polyphen predicts the variant to be probably damaging; Mutation Taster predicts it to be damaging in 4 of 4 transcripts; and SIFT predicts it to be deleterious. The threonine at codon 613 is highly conserved across species, as are neighboring amino acids. Several nearby variants have been reported in association with disease in the literature: Y611H, V612L, and A614V (note, none of these have been reviewed by SCICD team). This variant is located in exon 7 within the pore region of KCNH2. Mutations in KCNH2 cause long QT syndrome type 2 (LQT2). Thr613Met is currently present in HGMD as a disease-causing mutation. Jongbloed et al. (1999) screened 24 Dutch index patients and families with LQTS for mutations in KCNQ1 and KCNH2. They identified this variant in a patient whose father died during sleep and whose brother died before age 40 (trigger of syncope = acoustic). The authors note that this variant was novel at the time of the study. The authors also note that this missense mutation is situated in a CpG sequence, which are known as mutation-sensitive due to potential deamination of 5-methylcytosine at the CpG dinucleotides. The variant was absent from 55 control individuals in this study. This variant was also identified by Laitinen et al. (2000): They screened 39 Finnish LQTS patients, and identified the Thr613Met variant in one proband with LQTS. Notably, it was judged to be a de novo mutation, as it was absent from both parents. Mean QTc of this patient was 536 msec. Splawski et al. (2000) screened 262 unrelated individuals of North American and European ancestry with LQTS for mutations in 5 defined genes. They identified Thr613Met in 3 families with LQTS. It was not present in over 200 control individuals. Lupoglazoff et al. (2001) studied the T-wave morphology of 133 carriers of mutations in KCNQ1 and KCNH2 and also of 100 control individuals. Thr613Met was one of the KCNH2 variants that was present in the cohort but the authors do not specify how many unrelated individuals carried this particular variant. Moss et al. (2002) studied 201 subjects with genetically confirmed KCNH2 mutations derived from 51 LQT2 families from the International LQTS registry. This particular variant was identified in 1 subject. Simpson et al. (2009) identified this variant in a fetus who presented at 30 weeks gestation with VT at a rate of 220 beats/min and fetal hydrops. Despite rapid control of the arrhythmia the fetus developed severe periventricular leukomalacia before birth for which a poor neurological prognosis was given. The baby was delivered preterm at 32 weeks' gestation and died on the sixth day after birth. Long QT syndrome was identified postnatally on the electrocardiogram, and it was confirmed by genetic testing which showed a mutation in the KCNH2 gene (p.Thr613Met). The authors stated that the parents tested negative for the variant. Lupoglazoff et al. (2004) analyzed 23 neonate probands with LQTS and 2:1 AV block. They identified this variant by maternal transmission in 2 unrelated probands with LQTS and 2:1 AV block: one who was diagnosed after fetal bradycardia and torsades de pointes, with a QTc of 580; and another who presented with neonatal bradycardia and a QTc of 520. Shim et al. (2005): Studied 7 infants with LQTS. One infant presented at delivery with 2:1 AV block and was identified as having T613M in KCNH2 and P2005A in SCN5A (the father was a carrier of the P2005A variant, and the mother carried the T613M variant and had an ICD). Huang et al. (2001) sought to characterize the physiological consequences of three different LQTS-associated missense mutations, including Thr613Met, that are located in the pore helix of KCNH2. Mutant HERG subunits were heterologously expressed in Xenopus oocytes alone or in combination with wildtype HERG subunits. When expressed alone, T613M did not induce detectable currents. Coexpression of mutant and wildtype HERG subunits caused a dominant negative effect. This mutation reportedly prevented normal trafficking of the HERG protein to the surface membrane, as shown by the decrease in cell-surface chemiluminescence of HA-tagged mutant subunits compared with HA-tagged WT HERG subunits. The direction of the shifts in gating caused by T613Mwould be expected to cause a decrease in current beyond that resulting from a dominant negative induced suppression of channel function. In total, this variant is absent from ~6,755 control individuals (including ~6500 individuals of European and African American descent from the NHLBI ESP; 55 control individuals from Jongbloed et al. 1999; 200 control individuals from Splawski et al. 2000). This variant has the following legacy names: T273M; T613M; T517M.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10220144;PMID:10862094;PMID:10973849;PMID:11222472;PMID:11854117;PMID:12566525;PMID:14998624;PMID:15466642;PMID:15840476;PMID:16379539;PMID:16922724;PMID:17224687;PMID:18441445;PMID:19716085;PMID:19731233;PMID:19841300;PMID:22402334). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.