NM_172201.2(KCNE2):c.170T>C (p.Ile57Thr) AND not provided

Germline classification:: Likely benign (6 submissions)
Last evaluated:: Nov 18, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000058362.19

Allele description [Variation Report for NM_172201.2(KCNE2):c.170T>C (p.Ile57Thr)]

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

Genes:

KCNE2:potassium voltage-gated channel subfamily E regulatory subunit 2 [Gene - OMIM - HGNC]
LOC105372791:uncharacterized LOC105372791 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

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

Other names:

p.I57T:ATT>ACT

HGVS:

NC_000021.9:g.34370648T>C
NG_008804.1:g.11625T>C
NM_172201.2:c.170T>CMANE SELECT
NP_751951.1:p.Ile57Thr
NP_751951.1:p.Ile57Thr
LRG_291t1:c.170T>C
LRG_291:g.11625T>C
LRG_291p1:p.Ile57Thr
NC_000021.8:g.35742947T>C
NM_172201.1:c.170T>C
Q9Y6J6:p.Ile57Thr

Protein change:

I57T; ILE57THR

Links:

UniProtKB: Q9Y6J6#VAR_008378; OMIM: 603796.0003; dbSNP: rs74315448

NCBI 1000 Genomes Browser:

rs74315448

Molecular consequence:

NM_172201.2:c.170T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000089882	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (8) [See all records that cite these PMIDs] 10219239, 10984545, 14760488, 16922724, 19716085, 20042375, 22378279, 22581653
SCV000223518	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Nov 18, 2020)	germline	clinical testing	Citation Link,
SCV000699972	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (May 1, 2017)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 27884173, 23098067, 14760488, 11034315, 11101505, 10219239, 19716085, 24606995, 10984545, 24631775, 20042375, 19219384, 19863579, 26284702, 19841298, 10973849, 16922724 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001923928	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001928378	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV002037372	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

High prevalence of genetic variants previously associated with LQT syndrome in new exome data.

Refsgaard L, Holst AG, Sadjadieh G, Haunsø S, Nielsen JB, Olesen MS.

Eur J Hum Genet. 2012 Aug;20(8):905-8. doi: 10.1038/ejhg.2012.23. Epub 2012 Feb 29.

PubMed [citation]

PMID:: 22378279
PMCID:: PMC3400735

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]

PMID:: 22581653
PMCID:: PMC4640174

See all PubMed Citations (19)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089882.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (8)

Description

This variant has been reported in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:16922724;PMID:19716085;PMID:20042375;PMID:22378279).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000223518.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699972.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001923928.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001928378.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV002037372.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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