ClinVar Miner

Submissions for variant NM_172201.1(KCNE2):c.170T>C (p.Ile57Thr) (rs74315448)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000241603 SCV000319115 likely benign Cardiovascular phenotype 2017-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,Does not segregate with disease in family study (genes with incomplete penetrance),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Biesecker Lab/Human Development Section,National Institutes of Health RCV000148521 SCV000050774 likely benign Cardiac arrhythmia 2013-06-24 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148521 SCV000190233 uncertain significance Cardiac arrhythmia 2014-06-01 no assertion criteria provided research
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).
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
GeneDx RCV000212498 SCV000223518 uncertain significance not specified 2016-09-01 criteria provided, single submitter clinical testing The I57T variant in the KCNE2 gene has been published previously in association with LQTS (Abbott G et al., 1999; Kapplinger J et al., 2009). I57T was first reported in a 48 year old Hispanic female who had a prolonged QT interval of 470ms (Abbott G et al., 1999). The same study did not detect the I57T mutation in a control population of 1,010 individuals, and demonstrated that I57T diminished potassium flux through the channel (Abbott G et al., 1999). Another study reported the I57T mutation, which occurs in the transmembrane domain, in two unrelated individuals with LQTS and did not observe the mutation in over 2,600 reference alleles (Kapplinger J et al., 2009). However, the 1,000 Genomes Project identified I57T with an allele frequency of approximately 0.5% in individuals of African, European, and Asian ancestry, indicating I57T may be a rare benign variant. With the clinical and molecular information available at this time, we cannot definitively determine if I57T is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000006426 SCV000560071 likely benign Long QT syndrome 6 2017-05-08 criteria provided, single submitter clinical testing
OMIM RCV000006426 SCV000026609 pathogenic Long QT syndrome 6 1999-04-16 no assertion criteria provided literature only

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