rs1064793998
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_ModeratePP2PP3PM2_SupportingPS4_ModeratePP1_StrongPS3_Supporting
This summary comes from the ClinGen Evidence Repository: The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID:28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID:15677479). In summary, c.184G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_strong, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16618472/MONDO:0015967/086
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.184G>A | p.Val62Met | missense_variant | 2/10 | ENST00000403799.8 | |
GCK | NM_033507.3 | c.187G>A | p.Val63Met | missense_variant | 2/10 | ||
GCK | NM_033508.3 | c.181G>A | p.Val61Met | missense_variant | 3/11 | ||
GCK | NM_001354800.1 | c.184G>A | p.Val62Met | missense_variant | 2/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.184G>A | p.Val62Met | missense_variant | 2/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461804Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727194
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 21, 2021 | Variant summary: GCK c.184G>A (p.Val62Met) results in a conservative amino acid change located in the Hexokinase, N-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes. c.184G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus and has been shown to segregate with disease in several families (Gloyn_2005, Aloi_2017). These data indicate that the variant is very likely to be associated with disease. The variant has been reported in functional studies to result in lowered catalytic activity/impaired enzyme activity, decreased thermal stability and/or reduced aglucose affinity (Gloyn_2005, Arden_2007, Ralph_2009). Three 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Translational Genomics Laboratory, University of Maryland School of Medicine | Mar 12, 2018 | The c.184G>A variant in codon 62 (exon 3 of the RefSeqGene and of NM_000162.3) of the glucokinase gene, GCK, results in the substitution of Valine to Methionine. Missense mutations in GCK, including ones in this exon, have been reported in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256). The c.184G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.184G>A variant was previously shown to segregate with elevated fasting plasma glucose in three families (15677479, 27271189), A different amino acid substitution at this residue, p.Val62Ala, was shown to segregate with diabetes and impaired glucose tolerance in multiple individuals across four generations in a Norwegian family (9736233, 18399931). Additionally, multiple lines of computational evidence (MutationTaster, FATHMM, MetaSVM, MetalR, Provean, LRT, SIFT, Polyphen, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. Indeed, functional studies have demonstrated impaired enzyme activity of both the p.Val62Met and p.Val62Ala mutant proteins (15677479, 16731834, 17389332, 19187021). ACMG criteria = PP1strong, PS4mod, PS3, PM2, PP3 - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 17, 2023 | This variant has been identified in at least one individual with MODY and appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15677479, 16938872, 17389332, 19187021) - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2019 | Published functional studies predict lowered catalytic levels, decreased thermal stability, or reduced interaction with regulatory proteins (Arden et al., 2007; Ralph et al., 2009; Zelent et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19790256, 17389332, 19187021, 21831042, 16731834, 27271189, 28726111, 21104275, 18481947, 18322640, 17186219, 16938872, 15677479) - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 25, 2023 | The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID: 28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID: 15677479). In summary, c.184G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_strong, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at