Submissions for variant NM_172201.2(KCNE2):c.161T>C (p.Met54Thr)

gnomAD frequency: 0.00024  dbSNP: rs74315447

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212497	SCV000223517	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	Multiple functional studies demonstrate that p.(M54T) has a significant effect on potassium ion channel function in the heart (PMID: 19219384, 10219239, 12923204, 20042375); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20042375, 24569893, 24631769, 25333069, 10984545, 24631775, 26159999, 12923204, 19716085, 22677073, 23631727, 26859003, 28316956, 28794082, 10219239, 22378279, 25637381, 18006462, 14760488, 29661707, 30123799, 34426522, 19219384, 32078429, 34930020, 31235733, 23936059, 33626434, 31737537, 34247280, 33324689, 31447099, 25351510, 35125083, 34709746, 31980526)
Illumina Laboratory Services, Illumina	RCV000407848	SCV000435623	likely pathogenic	KCNE2-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	The KCNE2 c.161T>C (p.Met54Thr) variant has been reported in at least four studies in individuals with long QT syndrome (LQTS), drug-induced LQTS, or sudden unexplained death (SUD), and is found in a heterozygous state in six individuals (Abbot et al. 1999; Sesti et al. 2000; Kapplinger et al. 2009; Wang et al. 2014). The p.Met54Thr variant was also identified in two of over 6100 presumed healthy individuals (Freudenberg-Hua et al. 2014; Ghouse et al. 2015). The p.Met54Thr variant was absent from over 2300 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies indicated that the p.Met54Thr variant causes a reduction in current density in the potassium ion channel (Abbot et al. 1999; Sesti et al. 2000; Wu et al. 2010). Based on the collective evidence, the p.Met54Thr variant is classified as likely pathogenic for KCNE2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006425	SCV000770223	uncertain significance	Long QT syndrome 6	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the KCNE2 protein (p.Met54Thr). This variant is present in population databases (rs74315447, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KCNE2-related conditions (PMID: 10219239, 23936059, 26159999, 31737537, 33626434). ClinVar contains an entry for this variant (Variation ID: 6053). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNE2 function (PMID: 19219384, 20042375, 23631727, 31235733). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000006425	SCV000839965	risk factor	Long QT syndrome 6	2018-03-17	criteria provided, single submitter	clinical testing	This c.161T>C (p.Met54Thr) variant in the KCNE2 gene has been reported in patients with variable presentations such as arrythmias, sinus bradycardia and long QT syndrome [PMID 10219239, 19716085, 23631727]. This variant was first reported in a patient with atypical response to exercise with prolonged QTc intervals [PMID 10219239]. In vitro functional assays showed that the variant affect protein function [PMID 23631727, 20042375, 24569893]. This variant has been detected in 29 heterozygous individuals from Europe in the ExAC population database (http://exac.broadinstitute.org/variant/21-35742938-T-C). Methionine at amino acid position 54 of the KCNE2 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Met54Thr change to be deleterious. This variant is thus classified as a risk factor.
Ambry Genetics	RCV002399310	SCV002707364	likely benign	Cardiovascular phenotype	2020-02-18	criteria provided, single submitter	clinical testing	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.
Lildballe Lab, Aarhus University Hospital	RCV004772828	SCV005200532	uncertain significance	Long QT syndrome	2024-03-01	criteria provided, single submitter	research	PM2(s), PP2(m), PP3(s), BP6(s)
OMIM	RCV000006425	SCV000026608	pathogenic	Long QT syndrome 6	1999-04-16	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058360	SCV000089880	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:10219239;PMID:10984545;PMID:14760488;PMID:19716085;PMID:20042375;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV001841228	SCV000190230	likely pathogenic	Cardiac arrhythmia	2014-06-01	no assertion criteria provided	research