Variant summary: GCK c.1364T>A (p.Val455Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) 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 2.9e-05 in 238652 control chromosomes. c.1364T>A has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young 2 (e.g. Lukasova_2008, Gloyn_2009, Colclough_2022). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function suggesting that the variant has an inactivating effect on the protein and reduces activity (e.g. Gloyn_2008, Langer_2021). The most pronounced variant effect results in 10%-<30% of normal activity (Gloyn_2008) consistent with the established molecular mechanism of disease. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, with two citing the variant as uncertain significance, one citing the variant as likely pathogenic, and one citing the variant as pathogenic. Some submitters cite overlapping, but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.1364T>A (p.Val455Glu)
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.
(8)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(2)
Likely pathogenic(3); Uncertain significance(2)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000162.5(GCK):c.1364T>A (p.Val455Glu)
Variation ID: 585916 Accession: VCV000585916.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44184769 (GRCh37) [ NCBI UCSC ] 7: 44145170 (GRCh38) [ 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 20, 2018 Oct 20, 2024 Jan 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000162.5:c.1364T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Val455Glu missense NM_001354800.1:c.1364T>A NP_001341729.1:p.Val455Glu missense NM_001354801.1:c.353T>A NP_001341730.1:p.Val118Glu missense NM_001354802.1:c.224T>A NP_001341731.1:p.Val75Glu missense NM_001354803.2:c.398T>A NP_001341732.1:p.Val133Glu missense NM_033507.3:c.1367T>A NP_277042.1:p.Val456Glu missense NM_033508.3:c.1361T>A NP_277043.1:p.Val454Glu missense NC_000007.14:g.44145170A>T NC_000007.13:g.44184769A>T NG_008847.2:g.58001T>A LRG_1074:g.58001T>A LRG_1074t1:c.1364T>A LRG_1074p1:p.Val455Glu LRG_1074t2:c.1367T>A LRG_1074p2:p.Val456Glu - Protein change
- V455E, V456E, V118E, V133E, V454E, V75E
- Other names
- -
- Canonical SPDI
- NC_000007.14:44145169:A: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
- 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Jan 11, 2024 | RCV000711767.36 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 27, 2022 | RCV002469275.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003446380.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Mar 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842161.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Likely pathogenic
(Nov 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 2
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002765941.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: GCK c.1364T>A (p.Val455Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four … (more)
Variant summary: GCK c.1364T>A (p.Val455Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) 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 2.9e-05 in 238652 control chromosomes. c.1364T>A has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young 2 (e.g. Lukasova_2008, Gloyn_2009, Colclough_2022). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function suggesting that the variant has an inactivating effect on the protein and reduces activity (e.g. Gloyn_2008, Langer_2021). The most pronounced variant effect results in 10%-<30% of normal activity (Gloyn_2008) consistent with the established molecular mechanism of disease. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, with two citing the variant as uncertain significance, one citing the variant as likely pathogenic, and one citing the variant as pathogenic. Some submitters cite overlapping, but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003927524.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
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; … (more)
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: 18271687, 18481947, 31264968, 36400171, 36208030, 34789499, 19002431, 34662886, 34532767) (less)
|
|
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Uncertain significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002129033.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the GCK protein … (more)
This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the GCK protein (p.Val455Glu). This variant is present in population databases (rs753795627, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical history consistent with GCK-related conditions (PMID: 19002431, 25555642, 31264968, 34789499, 36400171; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 585916). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 18481947). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
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Likely pathogenic
(Apr 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001155071.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035523.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037348.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Maturity-onset diabetes of the young type 1
Affected status: yes
Allele origin:
germline
|
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV004174098.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
Comment:
Comment:
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: 18271687, 18481947, 31264968, 36400171, 36208030, 34789499, 19002431, 34662886, 34532767)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the GCK protein (p.Val455Glu). This variant is present in population databases (rs753795627, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical history consistent with GCK-related conditions (PMID: 19002431, 25555642, 31264968, 34789499, 36400171; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 585916). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 18481947). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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:
Variant summary: GCK c.1364T>A (p.Val455Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) 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 2.9e-05 in 238652 control chromosomes. c.1364T>A has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young 2 (e.g. Lukasova_2008, Gloyn_2009, Colclough_2022). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function suggesting that the variant has an inactivating effect on the protein and reduces activity (e.g. Gloyn_2008, Langer_2021). The most pronounced variant effect results in 10%-<30% of normal activity (Gloyn_2008) consistent with the established molecular mechanism of disease. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, with two citing the variant as uncertain significance, one citing the variant as likely pathogenic, and one citing the variant as pathogenic. Some submitters cite overlapping, but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
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: 18271687, 18481947, 31264968, 36400171, 36208030, 34789499, 19002431, 34662886, 34532767)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the GCK protein (p.Val455Glu). This variant is present in population databases (rs753795627, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical history consistent with GCK-related conditions (PMID: 19002431, 25555642, 31264968, 34789499, 36400171; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 585916). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 18481947). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Syndromic Monogenic Diabetes Genes Should Be Tested in Patients With a Clinical Suspicion of Maturity-Onset Diabetes of the Young. | Colclough K | Diabetes | 2022 | PMID: 34789499 |
| The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes. | Langer S | Diabetologia | 2021 | PMID: 34532767 |
| Residual β cell function and monogenic variants in long-duration type 1 diabetes patients. | Yu MG | The Journal of clinical investigation | 2019 | PMID: 31264968 |
| Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. | Bennett JT | Molecular genetics and metabolism | 2015 | PMID: 25555642 |
| Prevalence of GCK mutations in individuals screened for fasting hyperglycaemia. | Gloyn AL | Diabetologia | 2009 | PMID: 19002431 |
| Glucokinase (GCK) and other susceptibility genes for beta-cell dysfunction: the candidate approach. | Gloyn AL | Biochemical Society transactions | 2008 | PMID: 18481947 |
| Screening of mutations and polymorphisms in the glucokinase gene in Czech diabetic and healthy control populations. | Lukášová P | Physiological research | 2008 | PMID: 18271687 |
Text-mined citations for rs753795627 ...
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 Nov 03, 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.