The p.Tyr214X variant in GCK has been reported (as p.Tyr215X) in 1 individual wi th clinical features of gestational diabetes (Ellard 2000). This variant has als o been reported in ClinVar (Variation ID# 453007) and is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense v ariant leads to a premature termination codon, which is predicted to lead to a t runcated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in MODY. In summary, although additional studies a re required to fully establish its clinical significance, the p.Tyr214X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.645C>A (p.Tyr215Ter)
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.
(4)
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
4
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.645C>A (p.Tyr215Ter)
Variation ID: 453007 Accession: VCV000453007.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44149794 (GRCh38) [ NCBI UCSC ] 7: 44189393 (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 Dec 19, 2017 Sep 29, 2024 Apr 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000162.5:c.645C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Tyr215Ter nonsense NM_001354800.1:c.645C>A NP_001341729.1:p.Tyr215Ter nonsense NM_033507.3:c.648C>A NP_277042.1:p.Tyr216Ter nonsense NM_033508.3:c.642C>A NP_277043.1:p.Tyr214Ter nonsense NC_000007.14:g.44149794G>T NC_000007.13:g.44189393G>T NG_008847.2:g.53377C>A LRG_1074:g.53377C>A LRG_1074t1:c.645C>A LRG_1074p1:p.Tyr215Ter LRG_1074t2:c.648C>A LRG_1074p2:p.Tyr216Ter - Protein change
- Y215*, Y216*, Y214*
- Other names
- -
- Canonical SPDI
- NC_000007.14:44149793:G:T
-
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.
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0.00439 (A)
-
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 |
1091 | 1117 | |
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
|
Apr 19, 2024 | RCV000523346.8 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 2, 2023 | RCV000826165.6 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 29, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967703.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Tyr214X variant in GCK has been reported (as p.Tyr215X) in 1 individual wi th clinical features of gestational diabetes (Ellard 2000). This variant has … (more)
The p.Tyr214X variant in GCK has been reported (as p.Tyr215X) in 1 individual wi th clinical features of gestational diabetes (Ellard 2000). This variant has als o been reported in ClinVar (Variation ID# 453007) and is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense v ariant leads to a premature termination codon, which is predicted to lead to a t runcated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in MODY. In summary, although additional studies a re required to fully establish its clinical significance, the p.Tyr214X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002236305.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr215*) 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.Tyr215*) 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 clinical features of maturity-onset diabetes of the young (PMID: 30592380). ClinVar contains an entry for this variant (Variation ID: 453007). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004057901.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.Y215* pathogenic mutation (also known as c.645C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at … (more)
The p.Y215* pathogenic mutation (also known as c.645C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at nucleotide position 645. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in several individuals with maturity-onset diabetes of the young (Thomson KL et al. Hum Mutat, 2003 Nov;22:417; Sagen JV et al. Pediatr Diabetes, 2008 Oct;9:442-9; Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971; Patel KA et al. Diabetologia, 2022 Feb;65:336-342). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Apr 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000621860.4
First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024 |
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 … (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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36257325, 30592380, 34686905, 32533152) (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Tyr215*) 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 clinical features of maturity-onset diabetes of the young (PMID: 30592380). ClinVar contains an entry for this variant (Variation ID: 453007). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Y215* pathogenic mutation (also known as c.645C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at nucleotide position 645. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in several individuals with maturity-onset diabetes of the young (Thomson KL et al. Hum Mutat, 2003 Nov;22:417; Sagen JV et al. Pediatr Diabetes, 2008 Oct;9:442-9; Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971; Patel KA et al. Diabetologia, 2022 Feb;65:336-342). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36257325, 30592380, 34686905, 32533152)
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.Tyr214X variant in GCK has been reported (as p.Tyr215X) in 1 individual wi th clinical features of gestational diabetes (Ellard 2000). This variant has als o been reported in ClinVar (Variation ID# 453007) and is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense v ariant leads to a premature termination codon, which is predicted to lead to a t runcated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in MODY. In summary, although additional studies a re required to fully establish its clinical significance, the p.Tyr214X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Comment:
This sequence change creates a premature translational stop signal (p.Tyr215*) 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 clinical features of maturity-onset diabetes of the young (PMID: 30592380). ClinVar contains an entry for this variant (Variation ID: 453007). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Y215* pathogenic mutation (also known as c.645C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at nucleotide position 645. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in several individuals with maturity-onset diabetes of the young (Thomson KL et al. Hum Mutat, 2003 Nov;22:417; Sagen JV et al. Pediatr Diabetes, 2008 Oct;9:442-9; Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971; Patel KA et al. Diabetologia, 2022 Feb;65:336-342). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36257325, 30592380, 34686905, 32533152)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics. | Patel KA | Diabetologia | 2022 | PMID: 34686905 |
| Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia. | Wang Z | Journal of diabetes investigation | 2019 | PMID: 30592380 |
| Virtual Screening and Prediction of Binding of Caprine CSN1S2 Protein Tryptic Peptides to Glucokinase. | Fatchiyah F | Acta informatica medica : AIM : journal of the Society for Medical Informatics of Bosnia & Herzegovina : casopis Drustva za medicinsku informatiku BiH | 2017 | PMID: 29284910 |
| 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 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| 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 |
| Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. | Sagen JV | Pediatric diabetes | 2008 | PMID: 18399931 |
| Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. | Cuesta-Muñoz AL | Diabetes | 2004 | PMID: 15277402 |
| Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. | Njølstad PR | Diabetes | 2003 | PMID: 14578306 |
| Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY). | Thomson KL | Human mutation | 2003 | PMID: 14517956 |
| A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. | Ellard S | Diabetologia | 2000 | PMID: 10753050 |
| 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 |
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Text-mined citations for rs144723656 ...
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 08, 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.