ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.676G>A (p.Val226Met)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000162.5(GCK):c.676G>A (p.Val226Met)
Variation ID: 36243 Accession: VCV000036243.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44149763 (GRCh38) [ NCBI UCSC ] 7: 44189362 (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 Apr 4, 2013 May 1, 2024 Aug 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.676G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Val226Met missense NM_001354800.1:c.676G>A NP_001341729.1:p.Val226Met missense NM_033507.3:c.679G>A NP_277042.1:p.Val227Met missense NM_033508.3:c.673G>A NP_277043.1:p.Val225Met missense NC_000007.14:g.44149763C>T NC_000007.13:g.44189362C>T NG_008847.2:g.53408G>A LRG_1074:g.53408G>A LRG_1074t1:c.676G>A LRG_1074p1:p.Val226Met LRG_1074t2:c.679G>A LRG_1074p2:p.Val227Met P35557:p.Val226Met - Protein change
- V226M, V227M, V225M
- Other names
- NM_000162.5(GCK):c.676G>A
- Canonical SPDI
- NC_000007.14:44149762: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 |
1069 | 1094 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2022 | RCV000029906.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000255932.22 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2021 | RCV000825615.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2021 | RCV002477021.8 | |
Pathogenic (2) |
reviewed by expert panel
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Aug 13, 2023 | RCV003155042.8 |
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
(Aug 13, 2023)
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reviewed by expert panel
Method: curation
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Monogenic diabetes
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Monogenic Diabetes Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004032089.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) of NM_000162.5. GCK is … (more)
The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) 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 0.789, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and = 2 copies observed in the European non-Finnish population and = 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in more than 70 unrelated individuals with hyperglycemia (PS4; 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 negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with more than 20 informative meioses in more than 30 families (PP1_Strong; internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Val226Met variant has a relative activity index (RAI) of 0.009 to 0.198, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID: 10525657, 25015100, https://doi.org/10.1159/isbn.978-3-318-01080-0). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP2, PP4_Moderate, PP3, PM1. (less)
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Pathogenic
(Jul 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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MODY, type II
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000594954.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Likely pathogenic
(Oct 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Maturity-onset diabetes of the young type 2
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000891242.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: yes
Allele origin:
unknown
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV001656170.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
The c.676G>A (p.Val226Met, rs148311934) variant in exon 6 of GCK is a known pathogenic variant that has been reported in the medical literature (PMID: 17079173). … (more)
The c.676G>A (p.Val226Met, rs148311934) variant in exon 6 of GCK is a known pathogenic variant that has been reported in the medical literature (PMID: 17079173). This G to A transition results in the substitution of valine to methionine at amino acid position 226, which results in reduced enzymatic activity of glucokinase (PMID: 25015100). (less)
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Pathogenic
(Mar 10, 2022)
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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
Accession: SCV000613449.5
First in ClinVar: Dec 19, 2017 Last updated: Dec 31, 2022 |
Comment:
This is reported to be a founder variant in the Quebec region of Canada (PMID: 17079173), and is statistically more frequent in affected individuals than … (more)
This is reported to be a founder variant in the Quebec region of Canada (PMID: 17079173), and is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant resulted in reduced ATP affinity and catalytic activity that could be due to increased protein instability (PMID: 10426385, 10525657, 25015100). (less)
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Pathogenic
(Sep 24, 2021)
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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: SCV000894423.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 03, 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: SCV000322348.12
First in ClinVar: Oct 09, 2016 Last updated: Mar 11, 2023 |
Comment:
Published functional studies demonstrate a damaging effect leading to decreased enzyme activity of the glucokinase protein and may cause a milder phenotype by simultaneously increasing … (more)
Published functional studies demonstrate a damaging effect leading to decreased enzyme activity of the glucokinase protein and may cause a milder phenotype by simultaneously increasing its stability (Davis et al., 1999; Raimondo et al., 2014); Not observed at a 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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10426385, 25414397, 25306193, 25555642, 10525657, 20337973, 27080136, 27634015, 26897468, 16965331, 17079173, 9049484, 31957151, 32041611, 34108472, 25015100, 21569204, 22101819) (less)
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Pathogenic
(Jan 25, 2024)
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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: SCV002235206.3
First in ClinVar: Apr 07, 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 226 of the GCK protein (p.Val226Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the GCK protein (p.Val226Met). This variant is present in population databases (rs148311934, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 9049484, 12627330, 17079173, 19790256, 22335469, 25414397, 25555642, 31957151). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36243). 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 not expected to disrupt GCK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385, 10525657). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 04, 2021)
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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: SCV000966967.2
First in ClinVar: Aug 26, 2019 Last updated: Apr 20, 2024 |
Comment:
The p.Val225Met variant in GCK has been reported in >15 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least … (more)
The p.Val225Met variant in GCK has been reported in >15 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 8 affected members across 6 families (Velho 1997, Pruhova 2003, Henderson 2007, Delvecchio 2014, Alkorta-Aranburu 2014, Raimondo 2014, Bennett 2015; note that most studies report this variant as p.Val226Met). This variant has also been identified in 0.002% (2/113710) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact to protein function (Davis 1999, Miller 1999, Raimondo 2014). Furthermore, multiple amino acid changes at the same position (p.Val225Glu, p.Val225Leu) have been reported in individuals with MODY, suggesting that changes to this position may not be tolerated. Finally, this variant as been reported as Pathogenic in ClinVar (Variation ID 36243). In summary, the p.Val225Met variant meets criteria to be classified as pathogenic for autosomal dominant MODY based on case observations, segregation studies, low frequency in controls, and functional evidence. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Supporting. (less)
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Pathogenic
(Apr 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Maturity-onset diabetes of the young type 2
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002059773.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
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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: SCV002562189.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PS4, PP1_Strong, PS3_Moderate, PM2, PP2, PP4_Moderate, PP3, PM1
Number of individuals with the variant: 3
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Pathogenic
(Feb 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Monogenic diabetes
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052561.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 26, 2023 |
Comment:
Variant summary: GCK c.676G>A (p.Val226Met) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four … (more)
Variant summary: GCK c.676G>A (p.Val226Met) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251402 control chromosomes (gnomAD). c.676G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (example: Velho_1997, Pruhova_2010, Vits_2006). These data indicate that the variant is very likely to be associated with disease. Multiple reports have provided experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Examples: Davis_ 1999 and Miller_1999). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jul 13, 2020)
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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: SCV002662407.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.V226M variant (also known as c.676G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide … (more)
The p.V226M variant (also known as c.676G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 676. The valine at codon 226 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in multiple individuals with maturity-onset diabetes of the young (Velho G et al. Diabetologia, 1997 Feb;40:217-24; Vits L et al. Clin. Genet., 2006 Oct;70:355-9; Henderson M et al. Mol. Genet. Metab., 2007 Jan;90:87-92; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40). In addition, in vitro analyses by multiple groups have suggested that this variant affects enzyme kinetics including reduced activity (Miller SP et al. Diabetes, 1999 Aug;48:1645-51; Davis EA et al. Diabetologia, 1999 Oct;42:1175-86; Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40). 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 majority of available evidence to date, this variant is likely to be pathogenic. (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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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 |
Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children. | Xu A | Pediatric diabetes | 2020 | PMID: 31957151 |
Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. | Flannick J | Nature reviews. Endocrinology | 2016 | PMID: 27080136 |
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. | Bennett JT | Molecular genetics and metabolism | 2015 | PMID: 25555642 |
Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital. | Delvecchio M | Diabetes care | 2014 | PMID: 25414397 |
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 |
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. | Raimondo A | Human molecular genetics | 2014 | PMID: 25015100 |
MODY type 2 P59S GCK mutant: founder effect in South of Italy. | Delvecchio M | Clinical genetics | 2013 | PMID: 22335469 |
GCK-MODY (MODY 2) Caused by a Novel p.Phe330Ser Mutation. | Bonfig W | ISRN pediatrics | 2011 | PMID: 22389783 |
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 |
Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. | Osbak KK | Human mutation | 2009 | PMID: 19790256 |
Prevalence and clinical phenotype of the p.Val226Met glucokinase gene mutation in French Canadians in Quebec, Canada. | Henderson M | Molecular genetics and metabolism | 2007 | PMID: 17079173 |
Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. | Vits L | Clinical genetics | 2006 | PMID: 16965331 |
Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. | Feigerlová E | European journal of pediatrics | 2006 | PMID: 16602010 |
Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha. | Pruhova S | Diabetologia | 2003 | PMID: 12627330 |
Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis. | Davis EA | Diabetologia | 1999 | PMID: 10525657 |
Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype. | Miller SP | Diabetes | 1999 | PMID: 10426385 |
Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. | Velho G | Diabetologia | 1997 | PMID: 9049484 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a3bc2935-1bf2-4171-b759-ca1cfb249eb6 | - | - | - | - |
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Text-mined citations for rs148311934 ...
HelpRecord last updated Jun 02, 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.