Submissions for variant NM_172201.2(KCNE2):c.170T>C (p.Ile57Thr)

gnomAD frequency: 0.00063  dbSNP: rs74315448

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV001841229	SCV000050774	likely benign	Cardiac arrhythmia	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000058362	SCV000223518	likely benign	not provided	2020-11-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22378279, 10219239, 24796621, 24144883, 24055113, 25637381, 19841298, 20042375, 16922724, 19716085, 23382499, 10984545, 25696450, 19863579, 26159999, 24606995, 23098067, 19862833, 11101505, 11034315, 28341588, 27595200, 27884173, 29672598, 29032884, 28794082, 30986657, 31019283, 31320904, 31737537, 30847666)
Ambry Genetics	RCV000241603	SCV000319115	likely benign	Cardiovascular phenotype	2018-12-10	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.
Invitae	RCV000006426	SCV000560071	likely benign	Long QT syndrome 6	2023-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000058362	SCV000699972	likely benign	not provided	2017-05-01	criteria provided, single submitter	clinical testing	Variant summary: The KCNE2 c.170T>C (p.Ile57Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense change of Ile57 which is located in a predicted transmembrane domain. 5/5 in silico tools predict a damaging outcome for this variant, and functional studies indicate that this variant compromises function: 1) I57T-hMiRP1 diminished potassium flux through MiRP1/HERG channel complexes (Abbott_Cell_1999), 2) KCNE2-I57T decreased the rate of activation of the KCNQ1 current, abolished the hump of the tail currents upon repolarization, accelerated the deactivation process (127ms vs 552ms for WT), and shifted the voltage dependency of the channel activation towards more depolarized potentials (Tinel_EMBO_200), and 3) KCNQ2+KCNE2-I57T had a significantly increased (227ms vs 156ms for WT) time constant of deactivation (no significant change in time constant of activation), while KCNQ2+KCNQ3+KCNE2-I57T significantly decreased (68.0ms vs 99.5ms for WT) the time constant of activation (no significant change in time constant of deactivation; Tinel_FEBS_2000). However the variant 1) did not reduce mean current density of hMiRP1-Kv2.1 channels, 2) had no significant effect on V1/2 activation (McCrossan_J Membr Biol_2009), and 3) had the same sensitivity to oxatomide as wild type, thus the variant did not alter sensitivity to drug inhibition (Sesti_PNAS_2000). Furthermore, it has not been established if these quantitative and qualitative functional observations are sufficient to induce arrhythmia in the absence of other precipitating factors; therefore, this variant may only be a risk allele. This variant was found in 107/125050 control chromosomes (including one homozygote) including ExAC at a frequency of 0.0008557, which is approximately 128 times the estimated maximal expected allele frequency of a pathogenic KCNE2 variant (0.0000067), suggesting this variant is likely a benign polymorphism.This variant has been reported in many patients with LQTS and two reports of patients with drug induced LQTS, but majority of reports in the literature do not provide co-segregation data. This variant was found to in one neonate with mild LQTS and his two relatives (including mother) in one family, however clinical data was only provided for the proband that had a QT interval of 462ms as a newborn, but had normal QTc at follow-up (Schwartz_Circ_2009). The variant was reported in a patient with LQTS and neonatal seizures who also carried another pathogenic variant SCN5A R1623Q and the unaffected father, brother, and sister did not carry this KCNE2 c.170T>C variant, suggesting that this variant was not causative in this family (Heron_Epilepsia_2010). In another family with 5 affected WolffParkinsonWhite (WPW) syndrome, this variant was found in only 2 affected and also in 4 unaffected family members; a pathogenic MYH6 variant was found to co-segregate with disease in this family as well, thus suggesting that KCNE2 c.170T>C was not causative in this family (Bowels_AJMG_2015). In addition, two patients with primary electrical disease also carried another VUS, ANK2 p.His931Gln and CACNB2 p.Ala340Thr, respectively (Proost_2017). The variant is reported with conflicting classifications from multiple clinical diagnostic laboratories or databases, with the most recent reports being VUS and likely benign (2016). Recently, this variant was observed in six homozygotes who did not express phenotype from Saudi Human Genome Program (Abouelhoda_GenomeBiology_2016). Taken together, this the variant was classified as likely benign.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000006426	SCV000805126	uncertain significance	Long QT syndrome 6	2017-11-27	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000006426	SCV000883147	uncertain significance	Long QT syndrome 6	2018-11-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139401	SCV001299549	likely benign	Atrial fibrillation, familial, 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000006426	SCV001299550	likely benign	Long QT syndrome 6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000006426	SCV001367021	uncertain significance	Long QT syndrome 6	2019-01-24	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1.
PreventionGenetics, part of Exact Sciences	RCV004532298	SCV004718080	likely benign	KCNE2-related disorder	2022-02-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000006426	SCV000026609	pathogenic	Long QT syndrome 6	1999-04-16	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058362	SCV000089882	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:16922724;PMID:19716085;PMID:20042375;PMID:22378279).
CSER _CC_NCGL, University of Washington	RCV001841229	SCV000190233	uncertain significance	Cardiac arrhythmia	2014-06-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000006426	SCV001192584	uncertain significance	Long QT syndrome 6	2019-06-25	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000058362	SCV001923928	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000058362	SCV001928378	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058362	SCV002037372	likely benign	not provided		no assertion criteria provided	clinical testing