The p.Gln106Ter variant in GCK has not been previously reported in individuals with maturity-onset diabetes of the young and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 106, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.316C>T (p.Gln106Ter)
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
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.316C>T (p.Gln106Ter)
Variation ID: 972812 Accession: VCV000972812.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44152318 (GRCh38) [ NCBI UCSC ] 7: 44191917 (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 Jul 19, 2020 Apr 20, 2024 Nov 4, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000162.5:c.316C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Gln106Ter nonsense NM_001354800.1:c.316C>T NP_001341729.1:p.Gln106Ter nonsense NM_033507.3:c.319C>T NP_277042.1:p.Gln107Ter nonsense NM_033508.3:c.313C>T NP_277043.1:p.Gln105Ter nonsense NC_000007.14:g.44152318G>A NC_000007.13:g.44191917G>A NG_008847.2:g.50853C>T LRG_1074:g.50853C>T LRG_1074t1:c.316C>T LRG_1074p1:p.Gln106Ter LRG_1074t2:c.319C>T LRG_1074p2:p.Gln107Ter - Protein change
- Q107*, Q106*, Q105*
- Other names
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- Canonical SPDI
- NC_000007.14:44152317: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 (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 2, 2022 | RCV001249069.5 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 6, 2020 | RCV002464038.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 4, 2023 | RCV003558760.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423017.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Gln106Ter variant in GCK has not been previously reported in individuals with maturity-onset diabetes of the young and was absent from large population studies. … (more)
The p.Gln106Ter variant in GCK has not been previously reported in individuals with maturity-onset diabetes of the young and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 106, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). (less)
|
|
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Pathogenic
(Aug 02, 2022)
|
criteria provided, single submitter
Method: research
|
Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Geisinger Clinic, Geisinger Health System
Accession: SCV002562168.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PVS1, PM2, PP1, PS4, PP4
Number of individuals with the variant: 2
|
|
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Pathogenic
(-)
|
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: SCV002605308.1
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 rs2096281702 in MODY, yet. (less)
|
|
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Pathogenic
(Nov 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004295188.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln106*) in the GCK gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln106*) 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: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 19790256, 36227502). ClinVar contains an entry for this variant (Variation ID: 972812). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Likely Pathogenic
(Nov 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848497.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gln105Ter variant in GCK has been reported in 1 individual with maturity-onset diabetes of the young (MODY; Osbak 2009 PMID: 19790256) and was absent … (more)
The p.Gln105Ter variant in GCK has been reported in 1 individual with maturity-onset diabetes of the young (MODY; Osbak 2009 PMID: 19790256) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 105, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PM2. (less)
|
Comment:
Comment:
PVS1, PM2, PP1, PS4, PP4
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 rs2096281702 in MODY, yet.
Comment:
This sequence change creates a premature translational stop signal (p.Gln106*) 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: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 19790256, 36227502). ClinVar contains an entry for this variant (Variation ID: 972812). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Gln105Ter variant in GCK has been reported in 1 individual with maturity-onset diabetes of the young (MODY; Osbak 2009 PMID: 19790256) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 105, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PM2.
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:
The p.Gln106Ter variant in GCK has not been previously reported in individuals with maturity-onset diabetes of the young and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 106, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Comment:
PVS1, PM2, PP1, PS4, PP4
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 rs2096281702 in MODY, yet.
Comment:
This sequence change creates a premature translational stop signal (p.Gln106*) 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: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 19790256, 36227502). ClinVar contains an entry for this variant (Variation ID: 972812). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Gln105Ter variant in GCK has been reported in 1 individual with maturity-onset diabetes of the young (MODY; Osbak 2009 PMID: 19790256) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 105, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PM2.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| MODY patients carrying mutation in syndromic diabetes genes. An Italian single-center experience. | Marucci A | Acta diabetologica | 2023 | PMID: 36227502 |
| 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 |
| 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 |
| Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. | Raimondo A | Human molecular genetics | 2014 | PMID: 25015100 |
| De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. | Stanik J | Diabetologia | 2014 | PMID: 24323243 |
| 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 |
| Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. | Njølstad PR | Diabetes | 2003 | PMID: 14578306 |
| Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. | Postic C | The Journal of biological chemistry | 1999 | PMID: 9867845 |
| Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. | Grupe A | Cell | 1995 | PMID: 7553875 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4e0ffd32-1a1c-4e56-acd3-d993c7669a3b | - | - | - | - |
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Text-mined citations for rs2096281702 ...
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.