ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.766G>A (p.Glu256Lys)
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.766G>A (p.Glu256Lys)
Variation ID: 265175 Accession: VCV000265175.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44147747 (GRCh38) [ NCBI UCSC ] 7: 44187346 (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 10, 2016 Sep 16, 2024 Jul 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.766G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Glu256Lys missense NM_001354800.1:c.766G>A NP_001341729.1:p.Glu256Lys missense NM_033507.3:c.769G>A NP_277042.1:p.Glu257Lys missense NM_033508.3:c.763G>A NP_277043.1:p.Glu255Lys missense NC_000007.14:g.44147747C>T NC_000007.13:g.44187346C>T NG_008847.2:g.55424G>A LRG_1074:g.55424G>A LRG_1074t1:c.766G>A LRG_1074p1:p.Glu256Lys LRG_1074t2:c.769G>A LRG_1074p2:p.Glu257Lys P35557:p.Glu256Lys - Protein change
- E256K, E257K, E255K
- Other names
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- Canonical SPDI
- NC_000007.14:44147746: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
1089 | 1115 |
Conditions - Germline
Condition
Help
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
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2024 | RCV000255753.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763583.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV003493556.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003987481.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2019 | RCV004547644.1 |
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
(Oct 05, 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: SCV000613455.3
First in ClinVar: Oct 10, 2016 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with MODY. … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with MODY. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 18397317. (less)
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Pathogenic
(Jul 19, 2024)
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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: SCV000321715.10
First in ClinVar: Oct 10, 2016 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that … (more)
Not 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: 25306193, 23778137, 27634015, 28331372, 18397317, 36257325, 25555642, 34789499, 22101819, 15016359, 8446612, 23476789, 31957151, 20337973, 27913849, 23624530, 26123671, 17573900) (less)
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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: SCV000894422.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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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: SCV002525645.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
The c.766G>A variant in exon 7 of the GCK gene substitutes the glutamic acid with lysine at amino acid position 256 of the glucokinase protein. … (more)
The c.766G>A variant in exon 7 of the GCK gene substitutes the glutamic acid with lysine at amino acid position 256 of the glucokinase protein. This is a recurrent pathogenic variant that has been reported in the heterozygous state in several individuals with MODY. It is not a common variant in the general population (observed in 1 of 251,142 alleles; GnomAD v2.1). The p.Glu256Lys variant falls within the glucose binding site of GCK and has been experimentally demonstrated to cause a loss of catalytic activity. PMIDs: 25555642, 27634015, 28331372, 23476789, 8446612, NBK500456, 30225972, 21844708, 23771172 (less)
Clinical Features:
Hyperglycemia (present)
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004244361.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PS3,PS4,PM5,PM2_SUP,PP1,PP3
Clinical Features:
Hyperglycemia (present) , Diabetes mellitus (present)
Sex: male
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Pathogenic
(Dec 20, 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: SCV002245931.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 256 of the GCK protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 256 of the GCK protein (p.Glu256Lys). This variant is present in population databases (rs769268803, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (PMID: 17573900, 27634015, 28331372, 31957151). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265175). 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). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 11, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562624.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The GCK c.766G>A; p.Glu256Lys variant (rs769268803) is reported in the literature in multiple patients with maturity-onset diabetes of the young, type II (MODY2) and non-insulin-dependent … (more)
The GCK c.766G>A; p.Glu256Lys variant (rs769268803) is reported in the literature in multiple patients with maturity-onset diabetes of the young, type II (MODY2) and non-insulin-dependent diabetes (NIDDM), although no clear co-segregation is shown (Brahm 2016, Emelyanov 2017, Mirshahi 2022, Xu 2020). This variant is also reported in ClinVar (Variation ID: 265175) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Multiple lines of conformational and functional studies showed that this variant is part of the critical glucose binding domain (Yellapu 2013) and has profound impact on GCK catalytic activity ex vivo (Gidh-Jain 1993). Different amino acid substitutions at this residue (p.Glu256Ala, p.Glu256Asp, and p.Glu256Gly) have also been reported in patients with MODY2 and are considered to be disease-causing (Santana 2017, Garin 2008, Zmyslowska 2022). The glutamic acid at codon 256 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.977). Based on available information, the p.Glu256Lys variant is considered to be pathogenic. References: Brahm AJ et al. Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young. Can J Diabetes. 2016 Dec;40(6):555-560. PMID: 27634015. Garin I, et al. Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol (Oxf). 2008 Jun;68(6):873-8. PMID: 18248649. Gidh-Jain M, et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID: 8446612. Emelyanov AO et al. A glucokinase gene mutation in a young boy with diabetes mellitus, hyperinsulinemia, and insulin resistance. Int Med Case Rep J. 2017 Mar 7;10:77-80. PMID: 28331372. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Santana LS et al. Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families. Clin Genet. 2017 Oct;92(4):388-396. PMID: 28170077. Xu A et al. Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children. Pediatr Diabetes. 2020 May;21(3):431-440. PMID: 31957151. Yellapu NK et al. Structural Variations of Human Glucokinase Glu256Lys in MODY2 Condition Using Molecular Dynamics Study. Biotechnol Res Int. 2013;2013:264793. PMID: 23476789. Zmyslowska A et al. Next- generation sequencing is an effective method for diagnosing patients with different forms of monogenic diabetes. Diabetes Res Clin Pract. 2022 Jan;183:109154. PMID: 34826540. (less)
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Pathogenic
(Jan 08, 2024)
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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: SCV004804230.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: GCK c.766G>A (p.Glu256Lys) 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.766G>A (p.Glu256Lys) 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 4e-06 in 251142 control chromosomes (gnomAD). c.766G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (examples: Wajngot_1994, Estalella_2007 Brahm_2016, Emelyanov_2017, Colclough_2022) and at-least has been reported as a de novo occurrence (Emelyanov_2017). At least one publication reports experimental evidence that this variant impairs normal protein activity (Gidh-Jain_1993). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8446612, 17573900, 28331372, 27634015, 34789499, 7958490). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 12, 2019)
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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: SCV005043520.1
First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
The p.E256K pathogenic mutation (also known as c.766G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at … (more)
The p.E256K pathogenic mutation (also known as c.766G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 766. The glutamic acid at codon 256 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in multiple individuals and families with maturity-onset diabetes of the young (MODY) (Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Irgens HU et al. Diabetologia, 2013 Jul;56:1512-9). Based on structural analysis, this variant is anticipated to disrupt glucose binding, resulting in reduced activity (Pilkis SJ et al. J. Biol. Chem., 1994 Sep;269:21925-8; Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Yellapu NK et al. Biotechnol Res Int, 2013 Feb;2013:264793). Functional studies have illustrated this, by showing that E256K mutant protein has significantly reduced enzymatic activity (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Molnes J et al. FEBS J., 2008 May;275:2467-81). In addition, another alteration at the same codon, p.E256D, has been reported to cause MODY (Garin I et al. Clin. Endocrinol. (Oxf), 2008 Jun;68:873-8). Based on the supporting evidence, p.E256K is interpreted as a disease-causing mutation. (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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Syndromic Monogenic Diabetes Genes Should Be Tested in Patients With a Clinical Suspicion of Maturity-Onset Diabetes of the Young. | Colclough K | Diabetes | 2022 | PMID: 34789499 |
Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children. | Xu A | Pediatric diabetes | 2020 | PMID: 31957151 |
A glucokinase gene mutation in a young boy with diabetes mellitus, hyperinsulinemia, and insulin resistance. | Emelyanov AO | International medical case reports journal | 2017 | PMID: 28331372 |
Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. | Johansson BB | Diabetologia | 2017 | PMID: 27913849 |
Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young. | Brahm AJ | Canadian journal of diabetes | 2016 | PMID: 27634015 |
Single patient in GCK-MODY family successfully re-diagnosed into GCK-PNDM through targeted next-generation sequencing technology. | Antosik K | Acta diabetologica | 2016 | PMID: 26123671 |
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. | Bennett JT | Molecular genetics and metabolism | 2015 | PMID: 25555642 |
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 |
iPSC-derived β cells model diabetes due to glucokinase deficiency. | Hua H | The Journal of clinical investigation | 2013 | PMID: 23778137 |
Prevalence of monogenic diabetes in the population-based Norwegian Childhood Diabetes Registry. | Irgens HU | Diabetologia | 2013 | PMID: 23624530 |
Structural Variations of Human Glucokinase Glu256Lys in MODY2 Condition Using Molecular Dynamics Study. | Yellapu NK | Biotechnology research international | 2013 | PMID: 23476789 |
The active conformation of human glucokinase is not altered by allosteric activators. | Petit P | Acta crystallographica. Section D, Biological crystallography | 2011 | PMID: 22101819 |
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 |
Catalytic activation of human glucokinase by substrate binding: residue contacts involved in the binding of D-glucose to the super-open form and conformational transitions. | Molnes J | The FEBS journal | 2008 | PMID: 18397317 |
Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. | Garin I | Clinical endocrinology | 2008 | PMID: 18248649 |
Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. | Estalella I | Clinical endocrinology | 2007 | PMID: 17573900 |
Glucokinase: structural analysis of a protein involved in susceptibility to diabetes. | Pilkis SJ | The Journal of biological chemistry | 1994 | PMID: 8071309 |
Glucose potentiation of arginine-induced insulin secretion is impaired in subjects with a glucokinase Glu256Lys mutation. | Wajngot A | Diabetes | 1994 | PMID: 7958490 |
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 |
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Text-mined citations for rs769268803 ...
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.