ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.1099G>A (p.Val367Met)
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.1099G>A (p.Val367Met)
Variation ID: 381598 Accession: VCV000381598.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44145651 (GRCh38) [ NCBI UCSC ] 7: 44185250 (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 Mar 8, 2017 Feb 14, 2024 Aug 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.1099G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Val367Met missense NM_001354800.1:c.1099G>A NP_001341729.1:p.Val367Met missense NM_001354801.1:c.88G>A NP_001341730.1:p.Val30Met missense NM_001354802.1:c.-42G>A 5 prime UTR NM_001354803.2:c.133G>A NP_001341732.1:p.Val45Met missense NM_033507.3:c.1102G>A NP_277042.1:p.Val368Met missense NM_033508.3:c.1096G>A NP_277043.1:p.Val366Met missense NC_000007.14:g.44145651C>T NC_000007.13:g.44185250C>T NG_008847.2:g.57520G>A LRG_1074:g.57520G>A LRG_1074t1:c.1099G>A LRG_1074p1:p.Val367Met LRG_1074t2:c.1102G>A LRG_1074p2:p.Val368Met - Protein change
- V367M, V368M, V30M, V366M, V45M
- Other names
- NM_000162.5(GCK):c.1099G>A
- p.Val367Met
- Canonical SPDI
- NC_000007.14:44145650: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.
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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 |
1048 | 1073 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Apr 28, 2023 | RCV000440624.4 | |
Pathogenic (1) |
reviewed by expert panel
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Aug 9, 2023 | RCV003325955.2 |
Submissions - Germline
Classification
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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
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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
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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
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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 09, 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
Accession: SCV004032116.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
The c.1099G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 367 (p.(Val367Met)) of NM_000162.5. GCK is … (more)
The c.1099G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 367 (p.(Val367Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, 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 7 unrelated individuals with diabetes/hyperglycemia (PS4; PMID 27256595, 31968686, 9049484, internal lab contributors). This variant segregated with diabetes with 4 informative meioses in 3 families with diabetes/hyperglycemia (PP1_Strong; PMID 27256595, 9049484, 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%) (PP4; PMID 27256595 ). 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 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PS4, PP4, PP1_Strong. (less)
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Likely pathogenic
(Apr 11, 2016)
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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: SCV000521045.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The V367M variant in the GCK gene has been published previously in association with MODY (Velho et al., 1997). However, familial segregation data was not … (more)
The V367M variant in the GCK gene has been published previously in association with MODY (Velho et al., 1997). However, familial segregation data was not provided. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. V367M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that while V367M does not affect the GCK protein's metabolic response to glucose, it causes conformational changes and negatively affects the posttranscriptional regulation of the protein. (Ding et al., 2010; Markwardt et al., 2012) Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
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Likely pathogenic
(Aug 16, 2021)
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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: SCV002771529.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant affected interaction with other proteins leading to reduced response to glucose (PMID: 21454584). (less)
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Pathogenic
(Apr 28, 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: SCV004295143.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385, 10525657, 19934346, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385, 10525657, 19934346, 21454584, 26698632). 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. ClinVar contains an entry for this variant (Variation ID: 381598). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 9049484, 27256595; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 367 of the GCK protein (p.Val367Met). (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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MODY2 in Asia: analysis of GCK mutations and clinical characteristics. | Zhou Y | Endocrine connections | 2020 | PMID: 32375122 |
GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey. | Haliloglu B | Clinical endocrinology | 2016 | PMID: 27256595 |
Regulation of Glucokinase by Intracellular Calcium Levels in Pancreatic β Cells. | Markwardt ML | The Journal of biological chemistry | 2016 | PMID: 26698632 |
Association with nitric oxide synthase on insulin secretory granules regulates glucokinase protein levels. | Markwardt ML | Molecular endocrinology (Baltimore, Md.) | 2012 | PMID: 22771492 |
Glucagon-like peptide 1 stimulates post-translational activation of glucokinase in pancreatic beta cells. | Ding SY | The Journal of biological chemistry | 2011 | PMID: 21454584 |
Naturally occurring glucokinase mutations are associated with defects in posttranslational S-nitrosylation. | Ding SY | Molecular endocrinology (Baltimore, Md.) | 2010 | PMID: 19934346 |
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/e7250528-78fc-4419-81da-e7b6d944fc80 | - | - | - | - |
Text-mined citations for rs1057521092 ...
HelpRecord last updated Feb 20, 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.