Gene Validity Curation

GCK - monogenic diabetes

Gene: GCK (HGNC:4195)
Classification - 05/13/2020
Disease: monogenic diabetes (MONDO_0015967)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Monogenic Diabetes EP
Evidence Summary: GCK was first reported in relation to autosomal dominant monogenic diabetes in 1992 (Froguel et al., PMID: 1545870). The phenotype is specific to GCK and generally comprises lifelong stable, mild fasting hyperglycemia in the impaired fasting glucose to low diabetic range that generally neither responds to nor requires treatment, exhibits normal response to a glucose load, and has been associated with a much lower prevalence of the vascular complications typically seen with diabetes (PMID 24430320). This disease entity is often referred to as maturity-onset diabetes of the young (MODY) 2 (MODY2) and GCK-MODY, as well as GCK-associated hyperglycemia. For the association of GCK with MODY2 autosomal dominant monogenic diabetes, numerous variants have been reported in humans per ClinVar and variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs: 25555642, 1570017, 21104275, 23085272, 27269892, 27289208, 25850297). Segregation and familial inheritance has also been noted (PMIDs: 1545870, 23085272, 21104275, 1570017). Additional evidence is available in the literature, however the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function. This gene-disease relationship is also supported by expression studies, animal models, and in vitro functional assays. In summary, GCK is definitively associated with autosomal dominant monogenic diabetes (MODY2) or impaired fasting glucose with the specific phenotype noted above. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the GCK-related disease entities. Therefore, we have split curations for these disease entities. The present curation includes (1) Maturity-onset diabetes of the young (MODY) 2, MODY2 (MIM:125851) (due to heterozygous inactivating GCK variants). Other disease entities requiring separate curations include (2) Diabetes mellitus, permanent neonatal (MIM:606176) (due to homozygous or compound heterozygous GCK variants, usually requiring insulin treatment), and (3) Hyperinsulinemic hypoglycemia, familial, 3 (MIM:602485) (due to heterozygous activating GCK variants). Type 2 diabetes (polygenic; MIM:125853) will not be curated since the contribution of GCK is in the form of common variants with a small effect.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 2
3
3
Lopez AP et al. 2016 Aug (PMID:27289208);
Proband with predicted or proven null variant 1.5 0-2 10 4 6 6
Vionnet N et al. 1992 Apr 23 (PMID:1570017); Mota AJ et al. 2013 Jan 10 (PMID:23085272); Ping Xiao Y et al. 2016 Aug 1 (PMID:27269892);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 5
2.1
2.1
Shen Y et al. 2011 Mar (PMID:21104275); Ping Xiao Y et al. 2016 Aug 1 (PMID:27269892); Igudin EL et al. 2014 Mar-Apr (PMID:25850297); Bennett JT et al. 2015 Mar (PMID:25555642);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 25.11 12
Froguel P et al. 1992 Mar 12 (PMID:1545870); Vionnet N et al. 1992 Apr 23 (PMID:1570017); Shen Y et al. 2011 Mar (PMID:21104275); Mota AJ et al. 2013 Jan 10 (PMID:23085272);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 25.11    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
2
Velho G et al. 1992 Aug 22 (PMID:1354782);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Jetton TL et al. 1992 Apr 1 (PMID:1557365); Fagerberg L et al. 2014 Feb (PMID:24309898); GTEx Consortium et al. 2013 Jun (PMID:23715323);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 5 4
Bali D et al. 1995 Sep 15 (PMID:7665557); Pino MF et al. 2007 May 4 (PMID:17353190);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
06/09/2020
EXPERT CURATION (DATE)
Definitive
05/13/2020
EVIDENCE SUMMARY
GCK was first reported in relation to autosomal dominant monogenic diabetes in 1992 (Froguel et al., PMID: 1545870). The phenotype is specific to GCK and generally comprises lifelong stable, mild fasting hyperglycemia in the impaired fasting glucose to low diabetic range that generally neither responds to nor requires treatment, exhibits normal response to a glucose load, and has been associated with a much lower prevalence of the vascular complications typically seen with diabetes (PMID 24430320). This disease entity is often referred to as maturity-onset diabetes of the young (MODY) 2 (MODY2) and GCK-MODY, as well as GCK-associated hyperglycemia. For the association of GCK with MODY2 autosomal dominant monogenic diabetes, numerous variants have been reported in humans per ClinVar and variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs: 25555642, 1570017, 21104275, 23085272, 27269892, 27289208, 25850297). Segregation and familial inheritance has also been noted (PMIDs: 1545870, 23085272, 21104275, 1570017). Additional evidence is available in the literature, however the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function. This gene-disease relationship is also supported by expression studies, animal models, and in vitro functional assays. In summary, GCK is definitively associated with autosomal dominant monogenic diabetes (MODY2) or impaired fasting glucose with the specific phenotype noted above. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the GCK-related disease entities. Therefore, we have split curations for these disease entities. The present curation includes (1) Maturity-onset diabetes of the young (MODY) 2, MODY2 (MIM:125851) (due to heterozygous inactivating GCK variants). Other disease entities requiring separate curations include (2) Diabetes mellitus, permanent neonatal (MIM:606176) (due to homozygous or compound heterozygous GCK variants, usually requiring insulin treatment), and (3) Hyperinsulinemic hypoglycemia, familial, 3 (MIM:602485) (due to heterozygous activating GCK variants). Type 2 diabetes (polygenic; MIM:125853) will not be curated since the contribution of GCK is in the form of common variants with a small effect.