Description
The c.1190G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 397 (p.(Arg397Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:17186219 , internal lab contributors). This variant segregated with diabetes, with at least 7 informative meioses in 14 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:17186219). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg397Leu has RAI=0.72, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 17186219). This variant has been detected in the homozygous state in at least 5 individuals with neonatal diabetes (PM3; internal lab contributors). In summary, c.1190G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM3.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |