NM_000525.3(KCNJ11):c.67A>G (p.Lys23Glu)

NM_000525.3(KCNJ11):c.67A>G (p.Lys23Glu)

Variant type:
single nucleotide variant
Cytogenetic location:
11p15.1
Genomic location:
  • Chr11:17409572 (on Assembly GRCh37)
  • Chr11:17388025 (on Assembly GRCh38)
Protein change:
E23K, K23E
HGVS:
  • NG_012446.1:g.5635A>G
  • NM_001166290.1:c.-16-179A>G
  • NM_000525.3:c.67A>G
  • NC_000011.10:g.17388025T>C
  • NC_000011.9:g.17409572T>C
  • NP_000516.3:p.Lys23Glu
Links:
NCBI 1000 Genomes Browser:
rs5219
Molecular consequence:
  • NM_000525.3:c.67A>G: missense variant SO:0001583
  • NM_001166290.1:c.-16-179A>G: intron SO:0001627
Allele frequency:
  • GO-ESP 0.73810 (C)
  • GMAF 0.27410 (T)

Clinical significance

NM_000525.3(KCNJ11):c.67A>G (p.Lys23Glu)

Clinical significance:
conflicting data from submitters
Benign(1);drug response(1);risk factor(1)
Review status:
(0/4)0 stars out of maximum of 4 stars
conflicting data from submitters (classified by multiple submitters)
Number of submission(s):
3
Condition(s)
See supporting ClinVar records

1 Affected Gene

Recent Activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter
(Last submitted)
Submission accession
risk factor
(Nov 13, 2012)
classified by single submitter
(literature only)
literature onlygermlinePubMed (7)
OMIM
(Dec 30, 2010)
SCV000029432
drug response
(Nov 13, 2012)
classified by single submitter
(literature only)
literature only
  • Exercise stress response, impaired, association with
germlinePubMed (7)
OMIM
(Dec 30, 2010)
SCV000029433
Benign
(Jul 5, 2011)
classified by single submitter
(literature only)
literature onlynot providedPubMed (12)
GeneReviews
(Jan 8, 2013)
SCV000040740

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermline, not providednot providednot provided

GeneReviews

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providednot provided

Description

not provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

Association with Impaired Exercise Stress Response
Hani et al. (1998) identified a glu23-to-lys (E23K) amino acid substitution in the KCNJ11 gene by molecular screening using SSCP and direct sequencing in 72 French Caucasian type II diabetic families. They genotyped this variant in French cohorts of 191 unrelated type II diabetic probands and 119 normoglycemic control subjects and performed association studies. Homozygosity for lys23 (KK) was more frequent in type II diabetic than in control subjects (27 vs 14%; p = 0.015). Analyses in a recessive model (KK vs EK/EE) showed a stronger association of the K allele with diabetes. In a metaanalysis of their data for the E23K variant and data obtained from 3 other Caucasian groups, Hani et al. (1998) found the E23K variant to be significantly associated with type II diabetes.
Hansen et al. (2005) investigated the separate and combined effects of the PPARG pro12-to-ala (P12A; 601487.0002) and the KCNJ11 E23K polymorphisms on risk of type II diabetes. The combined analysis involved 1,164 type II diabetic patients and 4,733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of KCNJ11 E23K associated with type II diabetes (odds ratio, 1.19; P = 0.0002), whereas PPARG P12A showed no significant association with type 2 diabetes. The combined analysis indicated that the 2 polymorphisms acted in an additive manner to increase the risk of type II diabetes, and the authors found no evidence for a synergistic interaction between them. Together, the 2 polymorphisms conferred a population-attributable risk for type II diabetes of 28%. The authors concluded that their results showed no evidence of a synergistic interaction between the KCNJ11 E23K and PPARG P12A polymorphisms, but indicated that they may act in an additive manner to increase the risk of type II diabetes.
In genomewide association studies of type 2 diabetes involving genotype data from a variety of international consortia, the Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed association of the E23K polymorphism (rs5219) with diabetes susceptibility. Although this association was not strongly observed in any single scan, all-data metaanalyses resulted in genomewide significant association (OR = 1.14, P = 6.7 x 10(-11)).
Laukkanen et al. (2004) found an additive effect of a high risk ABCC8 (600509) haplotype, composed of a silent polymorphism (AGG-AGA; arg1273 to arg) and 3 promoter polymorphisms, and the 23K allele of the KCNJ11 gene.
Reyes et al. (2009) found that the E23K polymorphism was overrepresented in 115 individuals with dilated cardiomyopathy (see 115200) and congestive heart failure (CHF) compared to 2,031 community-based controls (p less than 0.001). In addition, the KK genotype, which was present in 18% of the CHF patients, was associated with abnormal cardiopulmonary exercise stress testing: despite similar baseline heart rates among genotype subgroups, individuals with the KK genotype had a significantly reduced heart rate increase at matched workload, at 75% of maximum oxygen consumption, and at peak VO(2), compared to those with the EE or EK genotypes. Noting that the glu23 residue is located within the functionally relevant intracellular slide helix region, Reyes et al. (2009) suggested that E23K might represent a biomarker for impaired stress performance.

Last Updated: Aug 5, 2014

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