Description
The c.1130G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 377 (p.(Arg377Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, 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 five unrelated individuals with hyperglycemia (PS4_Moderate: PMIDs: 21348868, 30245511, internal lab contributors). At least two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.(Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Arg377Leu). Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023) : PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
