ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.370G>A (p.Asp124Asn)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000162.5(GCK):c.370G>A (p.Asp124Asn)
Variation ID: 211073 Accession: VCV000211073.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44151069 (GRCh38) [ NCBI UCSC ] 7: 44190668 (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 5, 2015 Mar 16, 2024 Nov 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.370G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Asp124Asn missense NM_001354800.1:c.370G>A NP_001341729.1:p.Asp124Asn missense NM_033507.3:c.373G>A NP_277042.1:p.Asp125Asn missense NM_033508.3:c.367G>A NP_277043.1:p.Asp123Asn missense NC_000007.14:g.44151069C>T NC_000007.13:g.44190668C>T NG_008847.2:g.52102G>A LRG_1074:g.52102G>A LRG_1074t1:c.370G>A LRG_1074p1:p.Asp124Asn LRG_1074t2:c.373G>A LRG_1074p2:p.Asp125Asn - Protein change
- D124N, D125N, D123N
- Other names
- NM_000162.5(GCK):c.370G>A
- Canonical SPDI
- NC_000007.14:44151068: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
1072 | 1097 |
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 (2) |
criteria provided, single submitter
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Aug 2, 2022 | RCV000193215.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 26, 2024 | RCV000518229.12 | |
Pathogenic (3) |
reviewed by expert panel
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Nov 2, 2023 | RCV001248968.8 | |
Likely risk allele (1) |
criteria provided, single submitter
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- | RCV002464011.1 | |
GCK-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2023 | RCV003955153.1 |
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
(Nov 02, 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: SCV004102852.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The c.370G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 124 (p.(Asp124Asn)) of NM_000162.5. GCK … (more)
The c.370G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 124 (p.(Asp124Asn)) 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 0.817, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and one copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 14 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 22773699, internal lab contributors). This variant was identified in a at least three individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in five families (PP1_Strong; internal lab contributors). In summary, c.379G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. (less)
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Uncertain significance
(Apr 19, 2019)
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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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Athena Diagnostics
Accession: SCV000613426.2
First in ClinVar: Dec 19, 2017 Last updated: Jan 18, 2020 |
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Monogenic diabetes
(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: SCV001422800.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Asp124Asn variant in GCK has been reported in at least 6 individuals (including 1 Polish, 1 Czech, 1 German, and 2 Caucasian individuals) with … (more)
The p.Asp124Asn variant in GCK has been reported in at least 6 individuals (including 1 Polish, 1 Czech, 1 German, and 2 Caucasian individuals) with Monogenic Diabetes (PMID: 27106716, 22773699, 24918535, 20337973; DOI: 10.2337/db18-1509-P), and has been identified in 0.002893% (1/34564) of Latino chromosomes and 0.0008805% (1/113574) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759072800). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 211073). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP2, PP3 (Richards 2015). (less)
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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: SCV002562170.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PM2, PP3, PP1_Strong, PS4, PM5_Supporting, PP4, PP2
Number of individuals with the variant: 13
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Likely risk allele
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605273.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet … (more)
Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs759072800 in MODY, yet. (less)
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Likely pathogenic
(Jan 25, 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: SCV003800669.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: GCK c.370G>A (p.Asp124Asn) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Four … (more)
Variant summary: GCK c.370G>A (p.Asp124Asn) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) 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 251174 control chromosomes (gnomAD). c.370G>A has been reported in the literature in several individuals affected with Monogenic Diabetes (e.g. Osbak_2009, Pruhova_2010, Fendler_2014, Caswell_2020, Bonneford_2020, Bodis_2022, Gjesing_2022), including a family with multiple affected members (Bodis_2022), however the variant was also found in healthy control(s) (Bonneford_2020). In a recent large study evaluating UK Biobank data, the variant was found in 3/14622 diabetes cases and 10/185509 controls without diagnosis of diabetes (Billings_2022). These data indicate that the variant is likely to be associated with disease, but might also suggest a reduced penetrance. At least one publication also reported in vivo functional analysis (euglycemic-hyperinsulinemic clamp) performed in two carriers heterozygous for the D124N variant, and found impairments of insulin-secretion, with beta-cell function about 50% of the controls (Bodis_2022). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments, i.e. as VUS (n=2), likely pathogenic (n=1) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Apr 18, 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: SCV003919450.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
Identified in multiple unrelated patients in association with MODY; however, patient-specific clinical and segregation information is limited or not provided (Pruhova et al., 2010; Chakera … (more)
Identified in multiple unrelated patients in association with MODY; however, patient-specific clinical and segregation information is limited or not provided (Pruhova et al., 2010; Chakera et al., 2012; Tracz et al., 2014); Not observed 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: 34662886, 19790256, 22773699, 24918535, 36208030, 20337973, 27059371, 32533152, 35176401) (less)
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Pathogenic
(Jan 26, 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: SCV003440140.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 124 of the GCK protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 124 of the GCK protein (p.Asp124Asn). This variant is present in population databases (rs759072800, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 19790256, 20337973, 22773699, 24918535, 32533152, 35176401, 36257325; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 211073). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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GCK-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004772270.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GCK c.370G>A variant is predicted to result in the amino acid substitution p.Asp124Asn. This variant has been reported in multiple unrelated individuals with MODY … (more)
The GCK c.370G>A variant is predicted to result in the amino acid substitution p.Asp124Asn. This variant has been reported in multiple unrelated individuals with MODY (Supp. Table S1, Osbak et al 2009. PubMed ID: 19790256; Pruhova S et al 2010. PubMed ID: 20337973; Chakera AJ et al 2012. PubMed ID: 22773699; Supplementary Table 1, Carmody D et al 2016. PubMed ID: 27106716; Caswell RC et al 2020. PubMed ID: 32533152). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic by ClinGen monogenic diabetes variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/211073/). A different substitution at the same amino acid (p.Asp124His) has also been reported in patients with MODY (Supp. Table S1 at Osbak et al. 2009. PubMed ID: 19790256). In summary, this variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Dec 14, 2021)
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no assertion criteria provided
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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Genetic Services Laboratory, University of Chicago
Accession: SCV002072033.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
The p.Asp124Asn change affects a highly conserved amino acid residue located in a hexokinase domain of the GCK protein that is known to be functional. … (more)
The p.Asp124Asn change affects a highly conserved amino acid residue located in a hexokinase domain of the GCK protein that is known to be functional. The p.Asp124Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This particular amino acid change has been described in the literature in other patients with GCK related MODY (PMIDs: 27106716, 20337973, 24918535, 27059371). This particular sequence change has been described in the gnomAD database in two heterozygous individuals which corresponds to a population frequency of 0.00080% (dbSNP rs759072800). This sequence change is the likely cause of this patient's phenotype, however functional studies have not been performed to prove this conclusively. (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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14-fold increased prevalence of rare glucokinase gene variant carriers in unselected Danish patients with newly diagnosed type 2 diabetes. | Gjesing AP | Diabetes research and clinical practice | 2022 | PMID: 36400171 |
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 |
Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort. | Billings LK | Endocrinology, diabetes & metabolism | 2022 | PMID: 36208030 |
Hepatic energy metabolism in a family with a glucokinase gene mutation and dysglycemia. | Bódis K | Diabetes research and clinical practice | 2022 | PMID: 35176401 |
Exome sequencing and analysis of 454,787 UK Biobank participants. | Backman JD | Nature | 2021 | PMID: 34662886 |
Clinical implications of the glucokinase impaired function - GCK MODY today. | Hulín J | Physiological research | 2020 | PMID: 33129248 |
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes. | Bonnefond A | Nature metabolism | 2020 | PMID: 33046911 |
Noninvasive Fetal Genotyping by Droplet Digital PCR to Identify Maternally Inherited Monogenic Diabetes Variants. | Caswell RC | Clinical chemistry | 2020 | PMID: 32533152 |
MODY2 in Asia: analysis of GCK mutations and clinical characteristics. | Zhou Y | Endocrine connections | 2020 | PMID: 32375122 |
Association of a homozygous GCK missense mutation with mild diabetes. | Marucci A | Molecular genetics & genomic medicine | 2019 | PMID: 31197960 |
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 |
Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients. | Liu L | Metabolism: clinical and experimental | 2018 | PMID: 30257192 |
Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY). | Li X | BMC pediatrics | 2018 | PMID: 29510678 |
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 |
GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature. | Ping Xiao Y | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27269892 |
GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated. | Carmody D | Acta diabetologica | 2016 | PMID: 27106716 |
Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors. | Fendler W | Diabetologia | 2016 | PMID: 27059371 |
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 |
Evolution- and structure-based computational strategy reveals the impact of deleterious missense mutations on MODY 2 (maturity-onset diabetes of the young, type 2). | George DC | Theranostics | 2014 | PMID: 24578721 |
Less but better: cardioprotective lipid profile of patients with GCK-MODY despite lower HDL cholesterol level. | Fendler W | Acta diabetologica | 2014 | PMID: 24549415 |
Antenatal diagnosis of fetal genotype determines if maternal hyperglycemia due to a glucokinase mutation requires treatment. | Chakera AJ | Diabetes care | 2012 | PMID: 22773699 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d70a49ce-f350-41b3-98bb-5dd1799c4aa6 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e92e139f-6994-4774-beb3-99278185204a | - | - | - | - |
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Text-mined citations for rs759072800 ...
HelpRecord last updated May 19, 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.