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NM_000162.5(GCK):c.523G>A (p.Gly175Arg) AND Monogenic diabetes

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jul 30, 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:
RCV003318498.2

Allele description [Variation Report for NM_000162.5(GCK):c.523G>A (p.Gly175Arg)]

NM_000162.5(GCK):c.523G>A (p.Gly175Arg)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.523G>A (p.Gly175Arg)
Other names:
NM_000162.5(GCK):c.523G>A
HGVS:
  • NC_000007.14:g.44150025C>T
  • NG_008847.2:g.53146G>A
  • NM_000162.5:c.523G>AMANE SELECT
  • NM_001354800.1:c.523G>A
  • NM_033507.3:c.526G>A
  • NM_033508.3:c.520G>A
  • NP_000153.1:p.Gly175Arg
  • NP_001341729.1:p.Gly175Arg
  • NP_277042.1:p.Gly176Arg
  • NP_277043.1:p.Gly174Arg
  • LRG_1074t1:c.523G>A
  • LRG_1074t2:c.526G>A
  • LRG_1074:g.53146G>A
  • LRG_1074p1:p.Gly175Arg
  • LRG_1074p2:p.Gly176Arg
  • NC_000007.13:g.44189624C>T
  • NM_000162.3:c.523G>A
  • P35557:p.Gly175Arg
Protein change:
G174R
Links:
UniProtKB: P35557#VAR_003698; dbSNP: rs587780344
NCBI 1000 Genomes Browser:
rs587780344
Molecular consequence:
  • NM_000162.5:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.520G>A - 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
SCV004022341ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Pathogenic
(Jul 30, 2023) 		germlinecuration

Citation Link,

SCV004122237Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Oct 27, 2023) 		germlineclinical testing

PubMed (6)
[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

Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis.

Davis EA, Cuesta-Muñoz A, Raoul M, Buettger C, Sweet I, Moates M, Magnuson MA, Matschinsky FM.

Diabetologia. 1999 Oct;42(10):1175-86.

PubMed [citation]
PMID:
10525657

Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus.

Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P, et al.

N Engl J Med. 1993 Mar 11;328(10):697-702.

PubMed [citation]
PMID:
8433729
See all PubMed Citations (6)

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004022341.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.523G>A variant in the glucokinase gene, GCK causes an amino acid change of Gly to Arg at codon 210 (p.(Gly175Arg)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with diabetes (PS4; PMID: 29944009, 20337973, 26552609, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 4 families with diabetes (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Gly175Arg variant has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657). The nucleotide change c.523G>C, which causes the same amino acid change, has been classified as pathogenic for MODY by the ClinGen MDEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3, PS1.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122237.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: GCK c.523G>A (p.Gly175Arg) 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 250998 control chromosomes (gnomAD). c.523G>A has been reported in the literature in multiple individuals affected with maturity-onset diabetes of the young type 2 (Martin_2008, Pruhova_2010). These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and this variant results in low expressed protein level and enzymatic activity (Gidh-Jain_1993, Davis_1999). The following publications have been ascertained in the context of this evaluation (PMID: 8433729, 8068341, 10525657, 8446612, 18411240, 20337973). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as pathogenic (classified by ClinGen Monogenic Diabetes Variant Curation Expert Panel) and likely pathogenic. 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: May 1, 2024