ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.544G>A (p.Val182Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000162.5(GCK):c.544G>A (p.Val182Met)
Variation ID: 129144 Accession: VCV000129144.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44150004 (GRCh38) [ NCBI UCSC ] 7: 44189603 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 17, 2014 May 1, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.544G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Val182Met missense NM_001354800.1:c.544G>A NP_001341729.1:p.Val182Met missense NM_033507.3:c.547G>A NP_277042.1:p.Val183Met missense NM_033508.3:c.541G>A NP_277043.1:p.Val181Met missense NC_000007.14:g.44150004C>T NC_000007.13:g.44189603C>T NG_008847.2:g.53167G>A LRG_1074:g.53167G>A LRG_1074t1:c.544G>A LRG_1074p1:p.Val182Met LRG_1074t2:c.547G>A LRG_1074p2:p.Val183Met P35557:p.Val182Met - Protein change
- V182M, V183M, V181M
- Other names
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- Canonical SPDI
- NC_000007.14:44150003:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GCK | - | - |
GRCh38 GRCh37 |
1052 | 1077 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Sep 11, 2020 | RCV000117131.10 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000255191.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763586.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 20, 2023 | RCV002345419.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2022 | RCV001248908.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000337884.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Maturity-onset diabetes of the young type 2
Type 2 diabetes mellitus Hyperinsulinism due to glucokinase deficiency Permanent neonatal diabetes mellitus 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894425.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(May 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV000613440.3
First in ClinVar: Oct 09, 2016 Last updated: Jan 26, 2024 |
Comment:
This 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 … (more)
This 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) (less)
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Pathogenic
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002247025.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This 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). … (more)
This 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. (less)
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Pathogenic
(Nov 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848478.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The 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 … (more)
The 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. (less)
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Pathogenic
(Jan 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002649099.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The 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 … (more)
The 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. (less)
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Pathogenic
(Feb 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448738.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422601.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The 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 … (more)
The 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). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV002525647.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
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 … (more)
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). (less)
Clinical Features:
Polyuria (present) , Polydipsia (present) , Abdominal pain (present)
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: research
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Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Geisinger Clinic, Geisinger Health System
Accession: SCV002562177.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3
Number of individuals with the variant: 5
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Pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321714.9
First in ClinVar: Oct 09, 2016 Last updated: May 27, 2023 |
Comment:
Published functional studies demonstrate a damaging effect, with the presence of the variant causing significantly decreased glucokinase activity in comparison to wild-type (Gidh-Jain et al., … (more)
Published functional studies demonstrate a damaging effect, with the presence of the variant causing significantly decreased glucokinase activity in comparison to wild-type (Gidh-Jain et al., 1993; Davis et al., 1999; Inoue et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 8446612, 19790256, 23771172, 29510678, 33852230, 31957151, 31968686, 10525657, 29056535, 29284910, 25695774, 15102714, 14517956, 21395678, 25494859, 8433729, 25082184, 20337973, 30191644, 33046911, 32792356, 33878173, 36208030, 18056790, 25306193, 25555642, 35177841) (less)
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Pathogenic
(Sep 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Gestational diabetes
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002072032.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
DNA 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 … (more)
DNA 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) (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Targeted gene panel analysis of Japanese patients with maturity-onset diabetes of the young-like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes. | Yorifuji T | Journal of diabetes investigation | 2023 | PMID: 36504295 |
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. | Mirshahi UL | American journal of human genetics | 2022 | PMID: 36257325 |
Search for a time- and cost-saving genetic testing strategy for maturity-onset diabetes of the young. | Dusatkova P | Acta diabetologica | 2022 | PMID: 35737141 |
Clinical and genetic features of maturity-onset diabetes of the young in pediatric patients: a 12-year monocentric experience. | Passanisi S | Diabetology & metabolic syndrome | 2021 | PMID: 34496959 |
Sequencing Cell-free Fetal DNA in Pregnant Women With GCK-MODY. | Kwak SH | The Journal of clinical endocrinology and metabolism | 2021 | PMID: 34406393 |
Systematic Genetic Study of Youth With Diabetes in a Single Country Reveals the Prevalence of Diabetes Subtypes, Novel Candidate Genes, and Response to Precision Therapy. | Stankute I | Diabetes | 2020 | PMID: 32086287 |
Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations. | Alvelos MI | Journal of clinical medicine | 2020 | PMID: 31968686 |
Targeted sequencing identifies novel variants in common and rare MODY genes. | de Santana LS | Molecular genetics & genomic medicine | 2019 | PMID: 31595705 |
Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort. | Johnson SR | Pediatric diabetes | 2019 | PMID: 30191644 |
Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY). | Li X | BMC pediatrics | 2018 | PMID: 29510678 |
Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations. | Aykut A | Gene | 2018 | PMID: 29056535 |
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. | Bennett JT | Molecular genetics and metabolism | 2015 | PMID: 25555642 |
Adolescent non-adherence reveals a genetic cause for diabetes. | Carmody D | Diabetic medicine : a journal of the British Diabetic Association | 2015 | PMID: 25494859 |
Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes. | Gandica RG | Pediatric diabetes | 2015 | PMID: 25082184 |
Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. | Alkorta-Aranburu G | Molecular genetics and metabolism | 2014 | PMID: 25306193 |
Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. | Ellard S | Diabetologia | 2013 | PMID: 23771172 |
Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes. | McDonald TJ | Diabetic medicine : a journal of the British Diabetic Association | 2011 | PMID: 21395678 |
Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. | Pruhova S | Pediatric diabetes | 2010 | PMID: 20337973 |
Diabetes models by screen for hyperglycemia in phenotype-driven ENU mouse mutagenesis projects. | Aigner B | American journal of physiology. Endocrinology and metabolism | 2008 | PMID: 18056790 |
A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program. | Inoue M | Human molecular genetics | 2004 | PMID: 15102714 |
Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY). | Thomson KL | Human mutation | 2003 | PMID: 14517956 |
Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families. | Costa A | European journal of endocrinology | 2000 | PMID: 10754480 |
Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis. | Davis EA | Diabetologia | 1999 | PMID: 10525657 |
Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. | Byrne MM | The Journal of clinical investigation | 1994 | PMID: 8132752 |
Nonradioactive screening of glucokinase mutations in maturity onset diabetes of the young. | Blanché H | BioTechniques | 1994 | PMID: 8068341 |
Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. | Gidh-Jain M | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8446612 |
Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. | Froguel P | The New England journal of medicine | 1993 | PMID: 8433729 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GCK | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/116a7eeb-2295-46fb-afab-bf40add6e886 | - | - | - | - |
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Text-mined citations for rs587780345 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.