Description
The c.454T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 152 (p.(Phe152Leu)) 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 0.992, 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 seven unrelated individuals with hyperglycemia (PS4; PMID: 16965331, internal lab contributors]). This variant segregated with diabetes/hyperglycemia, with at least four informative meioses in two families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibody) (PP4_Moderate; internal lab contributors]). In summary, c.454T>C meets the criteria to be classified as a variant of pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4, PM2_Supporting, PP3, PP2, PP1_Strong.
| # | 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 |
