Description
The c.1144T>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 382 (p.(Cys382Gly)) 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 0.912, 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 segregated with diabetes, with 4 informative meioses in a family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). 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 negative antibodies and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). Another missense variant, c.1144T>C (p.Cys382Arg), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys382Gly)(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): PP2, PP3, PM2_Supporting, PP1_Moderate, PS4_Moderate, 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 |
