ClinVar Genomic variation as it relates to human health

Variant summary: KCNE2 c.29C>T (p.Thr10Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251330 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE2 causing Arrhythmia phenotype (7e-05), strongly suggesting that the variant is benign. c.29C>T has been reported in the literature in individuals affected with long QT syndrome and Brugada syndrome and also, in individuals with sudden unexplained deaths (e.g. Burashnikov_2010, Burns_2016, Christiansen_2016, Lieve_2013, Mellor_2017, Tester_2012). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In at least two studies presenting patients affected with long QT syndrome (Roberts_2017) and a patient affected with auditory stimulus-induced long QT syndrome (Gordon_2008), the variant was detected in affected probands but it was also detected in their asymptomatic family members and therefore, appeared to not segregate with disease. Furthermore, Gordon et al (2008) carried out functional assessment of the variant through usage of whole-cell voltage clamp of transfected Chinese Hamster ovary cells and showed baseline IKr current reduction and slower recovery from inactivation for T10M-MiRP1-hERG channels when compared with wild-type channels, however only mild changes in IKr when KCNE2-Thr10Met was co-expressed with wild-type KCNH2. At least two co-occurrences with other pathogenic variants have been reported (PKP2 c.397C>T, p.Q133* (internal testing) and KCNQ1 c.1781G>A, p.Arg594Gln (Roberts_2017)), providing supporting evidence for a benign outcome for this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and as likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

See Variant Classification Assertion Criteria.

The Thr10Met variant in KCNE2 has previously been reported in 2 individuals with Long QT syndrome; however, in one family this variant was also identified in a 76 year-old relative who had coronary artery disease, congestive heart failure, and hypertension, but a normal ECG (Tester 2005, Gordon 2008). Functional studies have shown that the Thr10Met variant moderately impacts protein function (Gordon 2008); however, this in vitro assay may not accurately represent biological function. Whether KCNE2 variants alone cause Long QT syndrome or only confer increased risk when combined with other risk alleles is currently unclear. In summary, there is insufficient evidence for pathogenicity of this variant, and additional studies are needed to fully assess its clinical significance.

The KCNE2 Thr10Met variant has been previously reported in probands with Long QT syndrome (Tester DJ, et al., 2005; Gordon E, et al., 2008; Lieve KV, et al., 2013). We have identified this variant in 2 probands. The first proband is of north-west European descent, has HCM and a second likely pathogenic variant in MYL2. Our second patient is of Ashkenazi Jewish descent and has a clinical diagnosis of long QT syndrome. The variant has been identified 63 times in the Genome Aggregation Database (MAF=0.0002; http://gnomad.broadinstitute.org/) and the Ashkenazi Jewish sub-population frequency is 0.0037, which is far higher than expected based on the prevalence of LQTS. In silico tools SIFT and PolyPhen2 predict this variant to be deleterious, but MutationTaster predicts it to be a 'polymorphism'. In summary based on the high allele frequency in the general population we classify KCNE2 Thr10Met as 'benign'.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are proposed mechanisms of disease in this gene and are associated with long QT syndrome 6 (MIM#613693) and familial atrial fibrillation (MIM#611493), respectively. However, this should be interpreted with caution as the gene-disease association for KCNE2 is currently unclear (PMIDs: 22166675, 26123744, 24796621, 28794082, 15368194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v2) (66 heterozygotes, 0 homozygotes) with a subpopulation frequency of 0.003 in the Ashkenazi Jewish population. (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.T10K variant has previously been reported in a patient with atrial fibrillation (PMID: 29805884). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. Although this variant has been identified in individuals with long QT syndrome and sudden unexplained death, it has more recently been re-classified as either a variant of uncertain significance or a likely benign variant (PMIDs: 18006462, 22677073, 28600387, 28794082, 32268277; ClinVar). (I) 1010 - Functional evidence for this variant is inconclusive. Patch clamp analysis in CHO cells demonstrated mild changes in the Ikr ventricular repolarization current when expressed in heterozygous state however the reliablity of this assay is questionable. Moreover, the use of CHO cells might not reflect the correct environment for testing a cardiac-related response (PMID: 18006462). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:18006462). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.