Submissions for variant NM_000162.5(GCK):c.1016A>G (p.Glu339Gly)

dbSNP: rs1057524903

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV000445412	SCV004697915	pathogenic	Monogenic diabetes	2024-02-28	reviewed by expert panel	curation	The c.1016A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glycine at codon 339 (p.(Glu339Gly)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; ClinVar: 393450, PMIDs: 18399931, 16731834, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 1 family (PP1; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.06, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 16731834). Another missense variant, c.1015G>A p.Glu339Lys, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1016A>G 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): PS4, PS3_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting, PP1.
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000445412	SCV000537120	pathogenic	Monogenic diabetes	2016-06-03	criteria provided, single submitter	clinical testing	The c.1016A>G variant in codon 339 (exon 8) of the glucokinase gene, GCK, results in the substitution of Glutamic acid to Glycine. This variant was originally reported to co-segregate with diabetes in a Norwegian family with a phenotype consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (16731834). It was subsequently shown to track with diabetes in six additional Norwegian families (18399931). Functional studies on recombinant p.(Glu339Gly) showed reduced enzyme activity and decreased affinity for glucose (16731834). A different amino acid substitution at this residue, p.(Glu339Lys), was found to track with the MODY2 phenotype across three generations of a Chinese family (21104275). Functional studies on p.(Glu339Lys) demonstrated decreased protein yield, lower glucose and ATP affinity, and decreased thermal stability compared to wildtype (21104275). The c.1016A>G variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, MutationAssessor, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS3, PM2, PM5, PP1, PP3