GCK p.Phe150Ser

The c.449T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 150 (p.(Phe150Ser)) 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 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.0.0 Popmax filtering allele frequency of 0 (below the MDEP threshold of 0.000003), and ≤ 2 copies observed in the European non-Finnish population and any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in at least 28 unrelated individuals with hyperglycemia (PS4; PMIDs: 15305805, 30191644, internal lab contributors). This variant segregated with hyperglycemia, with at least 19 informative meioses in multiple families (PP1_Strong; internal lab contributors). Another missense variant, c.449T>A p.Phe150Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Ser has a greater Grantham distance (PM5). In summary, c.449T>C 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): PS4, PP1_Strong, PM2_Supporting, PP3, PP2, PM5.