chr7-44150004-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4PM2_SupportingPS3_ModeratePP2PP3PP1PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.544G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 182 (p.(Val182Met)) 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 absent from gnomAD v2.1.1 (PM2_Supporting).This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional assays were performed where the MDEP wild type quality control measures were met, and showed that the relative activity Index (RAI) of this variant was 0.02, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID:10525657). Furthermore, this variant was identified in at least 12 unrelated individuals with hyperglycemia (PS4; PMID:8433729, 10754480, 14517956, 25306193, 29510678, 31968686, 34496959, 35737141). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and macrosomia in normoglycemic offspring) (PP4_Moderate; PMID:34406393). Additionally, this variant segregated with hyperglycemia with 2 informative meioses in 2 families (PP1; PMIDs: 25494859, 29510678). In summary, c.544G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 08/11/2023): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting, PS3_Moderate, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA152954/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

14
4
1

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCKNM_000162.5 linkc.544G>A p.Val182Met missense_variant Exon 5 of 10 ENST00000403799.8 NP_000153.1 P35557-1Q53Y25
GCKNM_033507.3 linkc.547G>A p.Val183Met missense_variant Exon 5 of 10 NP_277042.1 P35557-2
GCKNM_033508.3 linkc.541G>A p.Val181Met missense_variant Exon 6 of 11 NP_277043.1 P35557-3
GCKNM_001354800.1 linkc.544G>A p.Val182Met missense_variant Exon 5 of 11 NP_001341729.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkc.544G>A p.Val182Met missense_variant Exon 5 of 10 1 NM_000162.5 ENSP00000384247.3 P35557-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461660
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727100
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 20, 2024Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8446612, 19790256, 23771172, 29510678, 33852230, 31957151, 31968686, 29056535, 29284910, 25695774, 15102714, 14517956, 21395678, 25494859, 8433729, 20337973, 30191644, 33046911, 32792356, 33878173, 36208030, 18056790, 25306193, 25555642, 35177841, 25082184, 10525657, 35472491, 34789499, 36257325, 36504295) -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityFeb 20, 2018- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2025This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 182 of the GCK protein (p.Val182Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 8433729, 23771172, 30191644). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 129144). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 8446612, 10525657). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMay 24, 2023This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10525657) -
Pathogenic, criteria provided, single submitterclinical testingSeattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital-The c.544G>A (p.Val182Met, rs587780345) variant, located in exon 5 of the GCK gene, results in substitution of methionine for valine at amino acid position 182 of the protein. This variant has been reported as pathogenic in the literature and in ClinVar by multiple submitters (PMID: 8433729, 23771172, 30191644). Functional characterization has shown that this variant results in loss of glucokinase activity (PMID: 10525657). This variant is absent from large population controls (0 of >250,000 alleles tested; Genome Aggregation Database v2.1). -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 25, 2015- -
Maturity-onset diabetes of the young type 2 Pathogenic:2
Pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 22, 2020The p.Val182Met variant in GCK has been reported in at least 9 individuals with maturity-onset diabetes of the young (MODY) type 2, segregated with disease in 4 affected relatives from 2 families (PMID: 29510678, 20337973, 21395678, 25082184, 23771172, 25306193, 25494859), and was absent from large population studies. Animal models in mice have shown that this variant causes MODY type 2 (15102714, 18056790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for MODY type 2 in an autosomal dominant manner based on the phenotype of mouse models being consistent with human disease, the increased prevalence of the variant in affected individuals, including relatives, compared to controls, and computational evidence. ACMG/AMP Criteria applied: PS3_PM2, PS4_moderate, PP3, PP1 (Richards 2015). -
Pathogenic, criteria provided, single submitterresearchGeisinger Clinic, Geisinger Health SystemAug 02, 2022PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3 -
Maturity onset diabetes mellitus in young Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 20, 2023The p.V182M pathogenic mutation (also known as c.544G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 544. The valine at codon 182 is replaced by methionine, an amino acid with highly similar properties. This mutation was first reported to co-segregate with disease in two French MODY families (Froguel P et al. N. Engl. J. Med., 1993 Mar;328:697-702) and has subsequently been reported in multiple additional families (Costa A et al. Eur. J. Endocrinol., 2000 Apr;142:380-6; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Carmody D et al. Diabet. Med., 2015 Jun;32:e20-3). In addition, when expressed in E. coli and purified, mutant glucokinase carrying this mutation showed significantly decreased enzyme activity compared to wild-type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Davis EA et al. Diabetologia 1999 Oct;42(10):1175-86). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 06, 2020The p.Val181Met (also known as p.Val182Met) variant in GCK has been reported in >7 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in >2 relatives (Froguel 1993 PMID: 8433729; Pruhova 2010 PMID: 20337973; McDonald 2011 PMID: 21395678; Ellard 2013 PMID: 23771172; Alkorta-Aranburu 2014 PMID: 25306193; Carmody 2015 PMID: 25494859; Gandica 2015 PMID: 25082184; Li 2018 PMID: 29510678). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 129144) and was absent from large population studies. Animal models in mice have shown that this variant causes MODY (Davis 1999 PMID: 10525657; Inoue 2014 PMID: 15102714; Aigner 2018 PMID: 18056790) and computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PS3, PP3, PP1. -
Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1833104:Permanent neonatal diabetes mellitus;C1865290:Hyperinsulinism due to glucokinase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelFeb 07, 2025The c.544G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 182 (p.(Val182Met)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional assays were performed where the MDEP wild type quality control measures were met, and showed that the relative activity Index (RAI) of this variant was 0.02, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 10525657). Furthermore, this variant was identified in at least 12 unrelated individuals with hyperglycemia (PS4; PMID: 8433729, 10754480, 14517956, 25306193, 29510678, 31968686, 34496959, 35737141). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and macrosomia in normoglycemic offspring) (PP4_Moderate; PMID: 34406393). Additionally, this variant segregated with hyperglycemia with 2 informative meioses in 2 families (PP1; PMIDs: 25494859, 29510678). In summary, c.544G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 08/11/2023): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting, PS3_Moderate, PS4. -
Gestational diabetes Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoSep 11, 2020DNA sequence analysis of the GCK gene demonstrated a sequence change, c.544G>A, in exon 5 that results in an amino acid change, p.Val182Met. This sequence change has been previously described in several patients with GCK-related MODY (PMIDs: 8433729, 20337973, 23771172, 25494859 and 25555642). This sequence change is absent from the large population databases such as ExAC and gnoMAD (dbSNP rs587780345). The p.Val182Met change affects a highly conserved amino acid residue located in a domain of the GCK protein which is known to be functional (PMID: 8446612). The p.Val182Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
.;D;.;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
D;D;.;D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
.;H;.;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.8
.;D;D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
D;D;D;D;.
Vest4
0.96
MVP
0.98
MPC
2.2
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.89
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780345; hg19: chr7-44189603; API