ClinVar Genomic variation as it relates to human health

The c.1339dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 12 novel amino acids before encountering a stop codon (p.(Arg447ProfsTer12)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 a three generation family history of diabetes) (PP4_Moderate, internal lab contributor). While this variant was identified in one individual with diabetes, this does not meet the MDEP cutoff for PS4_Moderate. Additionally, this variant segregated with disease with one informative meiosis in this individual's family, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, the c.1339dup variant 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 6/7/2023x): PVS1, PP4_Moderate, PM2_Supporting.