Not found in the total gnomAD dataset, and the data is high quality (0/282820 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.626C>T (p.Thr209Met)
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.
(5)
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/Likely risk allele
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000162.5(GCK):c.626C>T (p.Thr209Met)
Variation ID: 804851 Accession: VCV000804851.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44149813 (GRCh38) [ NCBI UCSC ] 7: 44189412 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 19, 2020 May 1, 2024 Jul 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000162.5:c.626C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Thr209Met missense NM_001354800.1:c.626C>T NP_001341729.1:p.Thr209Met missense NM_033507.3:c.629C>T NP_277042.1:p.Thr210Met missense NM_033508.3:c.623C>T NP_277043.1:p.Thr208Met missense NC_000007.14:g.44149813G>A NC_000007.13:g.44189412G>A NG_008847.2:g.53358C>T LRG_1074:g.53358C>T LRG_1074t1:c.626C>T LRG_1074p1:p.Thr209Met LRG_1074t2:c.629C>T LRG_1074p2:p.Thr210Met - Protein change
- T208M, T210M, T209M
- Other names
- -
- Canonical SPDI
- NC_000007.14:44149812:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
1096 | 1122 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 28, 2023 | RCV000992057.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 12, 2022 | RCV002265919.1 | |
| Likely pathogenic/Likely risk allele (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2017 | RCV002354899.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001144026.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/282820 chr). Statistically enriched in patients compared to ethnically matched controls. Found … (more)
Not found in the total gnomAD dataset, and the data is high quality (0/282820 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. (less)
|
|
|
Pathogenic
(May 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Monogenic diabetes
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547878.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: GCK c.626C>T (p.Thr209Met) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Five of … (more)
Variant summary: GCK c.626C>T (p.Thr209Met) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain 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 251450 control chromosomes. c.626C>T has been reported in the literature in multiple individuals affected with Monogenic Diabetes, including at least one case where the variant was found to be de novo (Estalella_2007, Codner_2009, Bennett_2015, Gaal_2021). These data indicate that the variant is very likely to be associated with disease. 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)
|
|
|
Likely risk allele
(-)
|
criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
|
Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605193.1
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 rs1583599303 in MODY, yet. (less)
|
|
|
Pathogenic
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002239107.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 209 of the GCK protein (p.Thr209Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 209 of the GCK protein (p.Thr209Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hyperinsulinemic hypoglycemia (PMID: 8168652, 23352578, 25174781, 28371533). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 804851). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jul 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002655881.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.T209M variant (also known as c.626C>T), located in coding exon 6 of the GCK gene, results from a C to T substitution at nucleotide … (more)
The p.T209M variant (also known as c.626C>T), located in coding exon 6 of the GCK gene, results from a C to T substitution at nucleotide position 626. The threonine at codon 209 is replaced by methionine, an amino acid with similar properties. This variant was identified in multiple maturity-onset diabetes of the young families (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Alkorta-Aranburu G et al. Mol. Genet. Metab., 2014 Dec;113:315-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Comment:
Comment:
Variant summary: GCK c.626C>T (p.Thr209Met) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain 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 251450 control chromosomes. c.626C>T has been reported in the literature in multiple individuals affected with Monogenic Diabetes, including at least one case where the variant was found to be de novo (Estalella_2007, Codner_2009, Bennett_2015, Gaal_2021). These data indicate that the variant is very likely to be associated with disease. 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.
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 rs1583599303 in MODY, yet.
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 209 of the GCK protein (p.Thr209Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hyperinsulinemic hypoglycemia (PMID: 8168652, 23352578, 25174781, 28371533). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 804851). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.T209M variant (also known as c.626C>T), located in coding exon 6 of the GCK gene, results from a C to T substitution at nucleotide position 626. The threonine at codon 209 is replaced by methionine, an amino acid with similar properties. This variant was identified in multiple maturity-onset diabetes of the young families (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Alkorta-Aranburu G et al. Mol. Genet. Metab., 2014 Dec;113:315-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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:
Not found in the total gnomAD dataset, and the data is high quality (0/282820 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
Comment:
Variant summary: GCK c.626C>T (p.Thr209Met) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain 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 251450 control chromosomes. c.626C>T has been reported in the literature in multiple individuals affected with Monogenic Diabetes, including at least one case where the variant was found to be de novo (Estalella_2007, Codner_2009, Bennett_2015, Gaal_2021). These data indicate that the variant is very likely to be associated with disease. 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.
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 rs1583599303 in MODY, yet.
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 209 of the GCK protein (p.Thr209Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hyperinsulinemic hypoglycemia (PMID: 8168652, 23352578, 25174781, 28371533). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 804851). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.T209M variant (also known as c.626C>T), located in coding exon 6 of the GCK gene, results from a C to T substitution at nucleotide position 626. The threonine at codon 209 is replaced by methionine, an amino acid with similar properties. This variant was identified in multiple maturity-onset diabetes of the young families (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Alkorta-Aranburu G et al. Mol. Genet. Metab., 2014 Dec;113:315-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 |
| Preliminary screening of mutations in the glucokinase gene of Chinese patients with gestational diabetes. | Wang Z | Journal of diabetes investigation | 2018 | PMID: 28371533 |
| 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 |
| 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 |
| 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 |
| Three unreported glucokinase (GCK) missense mutations detected in the screening of thirty-two Brazilian kindreds for GCK and HNF1A-MODY. | Weinert LS | Diabetes research and clinical practice | 2014 | PMID: 25174781 |
| 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 |
| Hyperglycaemia and β-cell antibodies: is it always pre-type 1 diabetes? | d'Annunzio G | Diabetes research and clinical practice | 2013 | PMID: 23352578 |
| 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 |
| Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing type 1 diabetes mellitus. | Codner E | Pediatric diabetes | 2009 | PMID: 19309449 |
| 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 |
| Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype. | Miller SP | Diabetes | 1999 | PMID: 10426385 |
| Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. | Hager J | Diabetes | 1994 | PMID: 8168652 |
| Nonradioactive screening of glucokinase mutations in maturity onset diabetes of the young. | Blanché H | BioTechniques | 1994 | PMID: 8068341 |
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Text-mined citations for rs1583599303 ...
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 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.