ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.952G>A (p.Gly318Arg)
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.952G>A (p.Gly318Arg)
Variation ID: 585929 Accession: VCV000585929.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44146530 (GRCh38) [ NCBI UCSC ] 7: 44186129 (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 Oct 20, 2018 Feb 14, 2024 Jul 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.952G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Gly318Arg missense NM_001354800.1:c.952G>A NP_001341729.1:p.Gly318Arg missense NM_001354801.1:c.8+89G>A intron variant NM_033507.3:c.955G>A NP_277042.1:p.Gly319Arg missense NM_033508.3:c.949G>A NP_277043.1:p.Gly317Arg missense NC_000007.14:g.44146530C>T NC_000007.13:g.44186129C>T NG_008847.2:g.56641G>A LRG_1074:g.56641G>A LRG_1074t1:c.952G>A LRG_1074p1:p.Gly318Arg LRG_1074t2:c.955G>A LRG_1074p2:p.Gly319Arg - Protein change
- G318R, G319R, G317R
- Other names
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- Canonical SPDI
- NC_000007.14:44146529: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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- Links
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 |
1086 | 1112 |
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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Jul 25, 2023 | RCV000711789.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 23, 2021 | RCV001805831.2 |
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
(Dec 23, 2021)
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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: SCV002051328.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: GCK c.952G>A (p.Gly318Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five … (more)
Variant summary: GCK c.952G>A (p.Gly318Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) 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 247788 control chromosomes. c.952G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes presenting as MODY2 (Maturity Onset Diabetes of the Young) (example, Thomson_2003, Pruhova_2003, Feigeriova_2006, Dustakova_2012, Valentinova_2012, Gal_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Feb 16, 2022)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502879.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Nov 22, 2022)
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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: SCV002031111.2
First in ClinVar: Dec 12, 2021 Last updated: Dec 11, 2022 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this … (more)
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21348868, 33852230, 26641800, 12627330, 14517956, 20337973, 28012402, 28663157, 26552609, 24518839, 22289546, 24918535, 28842611, 29207974, 31416898, 30245511, 23433541, 34440516, 34556497, 22332836) (less)
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Likely pathogenic
(Jun 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Monogenic diabetes
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761528.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Nov 23, 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
Accession: SCV000842186.2
First in ClinVar: Oct 20, 2018 Last updated: Dec 31, 2022 |
Comment:
This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with … (more)
This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced affinity of the enzyme to glucose (PMID: 28842611). (less)
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Pathogenic
(Jul 25, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002235363.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GCK protein (p.Gly318Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GCK protein (p.Gly318Arg). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 585929). This missense change has been observed in individuals with maturity onset diabetes of the young (MODY) (PMID: 12627330, 22493702, 28663157, 29207974). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). (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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Gene Panel Sequencing of Patients With Monogenic Diabetes Brings to Light Genes Typically Associated With Syndromic Presentations. | Saint-Martin C | Diabetes | 2022 | PMID: 34556497 |
A Comprehensive Analysis of Hungarian MODY Patients-Part II: Glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases. | Gaál Z | Life (Basel, Switzerland) | 2021 | PMID: 34440516 |
Congenital Anomalies in Offspring of Maternal Glucokinase-Maturity-Onset Diabetes of the Young: A Case Report. | Rudland VL | Diabetes care | 2019 | PMID: 31416898 |
A new clinical screening strategy and prevalence estimation for glucokinase variant-induced diabetes in an adult Chinese population. | Ma Y | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30245511 |
Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. | Bansal V | BMC medicine | 2017 | PMID: 29207974 |
Evidence-based tailoring of bioinformatics approaches to optimize methods that predict the effects of nonsynonymous amino acid substitutions in glucokinase. | Šimčíková D | Scientific reports | 2017 | PMID: 28842611 |
Phenotype Heterogeneity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY) Patients. | Wędrychowicz A | Journal of clinical research in pediatric endocrinology | 2017 | PMID: 28663157 |
Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data. | Giuffrida FMA | Diabetes research and clinical practice | 2017 | PMID: 28012402 |
Genetic testing for monogenic diabetes using targeted next-generation sequencing in patients with maturity-onset diabetes of the young. | Szopa M | Polskie Archiwum Medycyny Wewnetrznej | 2015 | PMID: 26552609 |
Genetic variability of GCKR alters lipid profiles in children with monogenic and autoimmune diabetes. | Tracz A | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2014 | PMID: 24918535 |
Population-based estimates for double diabetes amongst people with glucokinase monogenic diabetes, GCK-MODY. | Fendler W | Diabetic medicine : a journal of the British Diabetic Association | 2014 | PMID: 24660669 |
Clinical utility gene card for: Maturity-onset diabetes of the young. | Colclough K | European journal of human genetics : EJHG | 2014 | PMID: 24518839 |
A novel glucokinase deletion (p.Lys32del) and five previously described mutations co-segregate with the phenotype of mild familial hyperglycaemia (MODY2) in Brazilian families. | Giuffrida FM | Diabetes research and clinical practice | 2013 | PMID: 23433541 |
Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia. | Valentínová L | PloS one | 2012 | PMID: 22493702 |
Ancestral mutations may cause a significant proportion of GCK-MODY. | Dusatkova P | Pediatric diabetes | 2012 | PMID: 22332836 |
Novel glucokinase mutations in patients with monogenic diabetes - clinical outline of GCK-MD and potential for founder effect in Slavic population. | Borowiec M | Clinical genetics | 2012 | PMID: 21348868 |
The influence of dietary carbohydrate content on glycaemia in patients with glucokinase maturity-onset diabetes of the young. | Klupa T | The Journal of international medical research | 2011 | PMID: 22289546 |
HDL cholesterol as a diagnostic tool for clinical differentiation of GCK-MODY from HNF1A-MODY and type 1 diabetes in children and young adults. | Fendler W | Clinical endocrinology | 2011 | PMID: 21521320 |
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 |
Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. | Feigerlová E | European journal of pediatrics | 2006 | PMID: 16602010 |
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 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 |
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Text-mined citations for rs193922340 ...
HelpRecord last updated Sep 29, 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.