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NM_000162.5(GCK):c.127C>T (p.Arg43Cys) AND Monogenic diabetes

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 13, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV003325972.3

Allele description [Variation Report for NM_000162.5(GCK):c.127C>T (p.Arg43Cys)]

NM_000162.5(GCK):c.127C>T (p.Arg43Cys)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.127C>T (p.Arg43Cys)
Other names:
NM_000162.5(GCK):c.127C>T; p.Arg43Cys
HGVS:
  • NC_000007.14:g.44153382G>A
  • NG_008847.2:g.49789C>T
  • NM_000162.5:c.127C>TMANE SELECT
  • NM_001354800.1:c.127C>T
  • NM_033507.3:c.130C>T
  • NM_033508.3:c.124C>T
  • NP_000153.1:p.Arg43Cys
  • NP_001341729.1:p.Arg43Cys
  • NP_277042.1:p.Arg44Cys
  • NP_277043.1:p.Arg42Cys
  • LRG_1074t1:c.127C>T
  • LRG_1074t2:c.130C>T
  • LRG_1074:g.49789C>T
  • LRG_1074p1:p.Arg43Cys
  • LRG_1074p2:p.Arg44Cys
  • NC_000007.13:g.44192981G>A
  • NC_000007.13:g.44192981G>A
  • NM_000162.3:c.127C>T
Protein change:
R42C
Links:
dbSNP: rs1486280029
NCBI 1000 Genomes Browser:
rs1486280029
Molecular consequence:
  • NM_000162.5:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.124C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004032096ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Aug 13, 2023) 		germlinecuration

Citation Link,

SCV004813475Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Feb 21, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.

Wang Z, Diao C, Liu Y, Li M, Zheng J, Zhang Q, Yu M, Zhang H, Ping F, Li M, Xiao X.

J Diabetes Investig. 2019 Jul;10(4):963-971. doi: 10.1111/jdi.13001. Epub 2019 Feb 1.

PubMed [citation]
PMID:
30592380
PMCID:
PMC6626954

Novel glucokinase mutations in patients with monogenic diabetes - clinical outline of GCK-MD and potential for founder effect in Slavic population.

Borowiec M, Antosik K, Fendler W, Deja G, Jarosz-Chobot P, Mysliwiec M, Zmyslowska A, Malecki M, Szadkowska A, Mlynarski W.

Clin Genet. 2012 Mar;81(3):278-83. doi: 10.1111/j.1399-0004.2011.01656.x. Epub 2011 Mar 18.

PubMed [citation]
PMID:
21348868

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004032096.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.127C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 43 (p.(Arg43Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.924, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, established functional studies demonstrated the p.Arg43Cys protein has a relative activity index (RAI) < 0.5, indicating that this variant impacts protein function (PS3_Moderate; PMID: 25015100). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least eight unrelated individuals with hyperglycemia/diabetes (PS4; PMIDs: 30592380, 21348868, PMID 23771172, 25015100). One of these individuals was homozygous for c.127C>T and had permanent neonatal diabetes mellitus (PNDM) and negative testing for ABCC8, KCNJ11, INS and EIF2AK3 (PP4; PMID 25015100). This variant also segregated with diabetes/hyperglycemia, with 5 informative meioses in one family (PP1_Strong; PMID 21348868). Another missense variant, c.128G>A (p.Arg43His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg43Cys has a greater Grantham distance (PM5). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PM5, PP2, PP3, PP4, PM2_Supporting, PS3_Moderate.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813475.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: GCK c.127C>T (p.Arg43Cys) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes. c.127C>T has been reported in the literature in multiple heterozygous individuals affected with Monogenic Diabetes (e.g. Boroweic_2012, Wang_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing decreased catalytic activity in vitro (e.g. Wang_2019). The most pronounced variant effect results in 30%-50% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 21348868, 30592380). ClinVar contains an entry for this variant (Variation ID: 585911). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024