ClinVar

Description

The c.790G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 264 (p.(Gly264Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 11508276, 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 antibodies) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; PMID: 16026363s, internal lab contributors). This variant has been detected in two individuals with neonatal diabetes. Both were compound heterozygous (confirmed in trans) for this variant and another variant classified as pathogenic by ClinGen MDEP (PM3_Strong; PMIDs: 14578306, 16026363, internal lab contributors). 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 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Relative Activity Index (RAI) of this variant was found to be above the MDEP cutoff (0.5) for PS3_Moderate. While the p.Gly264Ser variant has been reported to cause protein misfolding, this is not considered to meet criteria for applying PS3_Supporting by the ClinGen MDEP (PMIDs: 22820548, 14578306, 16731834, https://doi.org/10.1159/000079009). In summary, c.790G>A 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): PP1_Strong, PS4, PP4_Moderate, PM3_Strong, PP2, PP3, PM2_Supporting.