Description
The c.1064T>C variant in the glucokinase gene, GCK, causes an amino acid change of Leucine to Proline at codon 355 (p.(Leu355Pro)) 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 0.9689, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, as well as in two individuals in ClinVar whose clinical status was not known DOI:10.1055/s-2004-819152, ClinVar ID 804832, internal lab contributor). However, PS4_Moderate cannot be applied because the number of affected individuals is below the ClinGen MDEP threshold. This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, the evidence supports the classification of c.1064T>C as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PP2, PP3, PM2_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 |
