Converted during submission to Likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.76C>T (p.Gln26Ter)
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000162.5(GCK):c.76C>T (p.Gln26Ter)
Variation ID: 36256 Accession: VCV000036256.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44153433 (GRCh38) [ NCBI UCSC ] 7: 44193032 (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 Oct 8, 2024 Aug 2, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000162.5:c.76C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Gln26Ter nonsense NM_001354800.1:c.76C>T NP_001341729.1:p.Gln26Ter nonsense NM_033507.3:c.79C>T NP_277042.1:p.Gln27Ter nonsense NM_033508.3:c.73C>T NP_277043.1:p.Gln25Ter nonsense NC_000007.14:g.44153433G>A NC_000007.13:g.44193032G>A NG_008847.2:g.49738C>T LRG_1074:g.49738C>T LRG_1074t1:c.76C>T LRG_1074p1:p.Gln26Ter LRG_1074t2:c.79C>T LRG_1074p2:p.Gln27Ter - Protein change
- Q26*, Q27*, Q25*
- Other names
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- Canonical SPDI
- NC_000007.14:44153432:G:A
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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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| GCK | - | - |
GRCh38 GRCh37 |
1093 | 1119 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 2, 2022 | RCV000029919.10 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2021 | RCV000255007.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002326691.1 | |
|
GCK-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Sep 29, 2024 | RCV004751228.1 |
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
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000343033.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002067466.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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likely pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
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MODY2
(autosomal dominant)
Affected status: yes, unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052574.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Likely pathogenic.
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Tissue: Blood
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
National Newborn Screening Laboratory, Hospital Nacional de Niños
Accession: SCV002506584.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
This is a nonsense variant in the GCK gene, where loss of function is a known mechanism of disease (PVS1). This variant results in a … (more)
This is a nonsense variant in the GCK gene, where loss of function is a known mechanism of disease (PVS1). This variant results in a truncated protein by creating a premature stop codon. It is not present in population databases (GnomAD exomes, GnomAD genomes) (PM2). (less)
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Pathogenic
(Nov 17, 2020)
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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: SCV000322349.6
First in ClinVar: Oct 09, 2016 Last updated: Dec 15, 2018 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11508276, 14981344, 25525159, 24735133) (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: SCV002562192.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PVS1, PM2, PP1, PS4
Number of individuals with the variant: 1
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Pathogenic
(-)
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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: SCV002601608.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 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 rs193922329 in MODY, yet. (less)
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Pathogenic
(Apr 23, 2021)
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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: SCV002238461.3
First in ClinVar: Apr 07, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 24735133, … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 24735133, 11508276, 24804978, 28726111). ClinVar contains an entry for this variant (Variation ID: 36256). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln26*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 24323243). (less)
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Pathogenic
(Sep 29, 2024)
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no assertion criteria provided
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: SCV005358582.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The GCK c.76C>T variant is predicted to result in premature protein termination (p.Gln26*). This variant has been reported in several individuals with maturity-onset diabetes of … (more)
The GCK c.76C>T variant is predicted to result in premature protein termination (p.Gln26*). This variant has been reported in several individuals with maturity-onset diabetes of the young (MODY) (Massa et al. 2001. PubMed ID: 11508276; Costantini et al. 2014. PubMed ID: 24735133; Table S1, Mirshahi et al. 2022. PubMed ID: 36257325; Yorifuji et al. 2022. PubMed ID: 36504295), in an individual with type 2 diabetes (Table S6, Jurgens et al. 2022. PubMed ID: 35177841), and in three individuals with monogenic diabetes (Vaxillaire et al. 2020. PubMed ID: 33242514). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in GCK are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
This is a nonsense variant in the GCK gene, where loss of function is a known mechanism of disease (PVS1). This variant results in a truncated protein by creating a premature stop codon. It is not present in population databases (GnomAD exomes, GnomAD genomes) (PM2).
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11508276, 14981344, 25525159, 24735133)
Comment:
PVS1, PM2, PP1, PS4
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 . However, there is no sufficient evidence to ascertain the significance of rs193922329 in MODY, yet.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 24735133, 11508276, 24804978, 28726111). ClinVar contains an entry for this variant (Variation ID: 36256). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln26*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 24323243).
Comment:
The GCK c.76C>T variant is predicted to result in premature protein termination (p.Gln26*). This variant has been reported in several individuals with maturity-onset diabetes of the young (MODY) (Massa et al. 2001. PubMed ID: 11508276; Costantini et al. 2014. PubMed ID: 24735133; Table S1, Mirshahi et al. 2022. PubMed ID: 36257325; Yorifuji et al. 2022. PubMed ID: 36504295), in an individual with type 2 diabetes (Table S6, Jurgens et al. 2022. PubMed ID: 35177841), and in three individuals with monogenic diabetes (Vaxillaire et al. 2020. PubMed ID: 33242514). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in GCK are expected to be pathogenic. This variant is interpreted as pathogenic.
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. |
Comment:
Converted during submission to Likely pathogenic.
Comment:
This is a nonsense variant in the GCK gene, where loss of function is a known mechanism of disease (PVS1). This variant results in a truncated protein by creating a premature stop codon. It is not present in population databases (GnomAD exomes, GnomAD genomes) (PM2).
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11508276, 14981344, 25525159, 24735133)
Comment:
PVS1, PM2, PP1, PS4
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 . However, there is no sufficient evidence to ascertain the significance of rs193922329 in MODY, yet.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 24735133, 11508276, 24804978, 28726111). ClinVar contains an entry for this variant (Variation ID: 36256). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln26*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 24323243).
Comment:
The GCK c.76C>T variant is predicted to result in premature protein termination (p.Gln26*). This variant has been reported in several individuals with maturity-onset diabetes of the young (MODY) (Massa et al. 2001. PubMed ID: 11508276; Costantini et al. 2014. PubMed ID: 24735133; Table S1, Mirshahi et al. 2022. PubMed ID: 36257325; Yorifuji et al. 2022. PubMed ID: 36504295), in an individual with type 2 diabetes (Table S6, Jurgens et al. 2022. PubMed ID: 35177841), and in three individuals with monogenic diabetes (Vaxillaire et al. 2020. PubMed ID: 33242514). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in GCK are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Clinical implications of the glucokinase impaired function - GCK MODY today. | Hulín J | Physiological research | 2020 | PMID: 33129248 |
| 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 |
| 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 |
| Glucokinase mutations in pediatric patients with impaired fasting glucose. | Aloi C | Acta diabetologica | 2017 | PMID: 28726111 |
| 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 |
| Genetic and bioinformatics analysis of four novel GCK missense variants detected in Caucasian families with GCK-MODY phenotype. | Costantini S | Clinical genetics | 2015 | PMID: 24735133 |
| Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients. | Kawakita R | Diabetic medicine : a journal of the British Diabetic Association | 2014 | PMID: 24804978 |
| De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. | Stanik J | Diabetologia | 2014 | PMID: 24323243 |
| MODY 2: mutation identification and molecular ancestry in a Brazilian family. | Mota AJ | Gene | 2013 | PMID: 23085272 |
| Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. | Gloyn AL | Human mutation | 2003 | PMID: 14517946 |
| High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. | Massa O | Diabetologia | 2001 | PMID: 11508276 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GCK | - | - | - | - |
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Text-mined citations for rs193922329 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 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.