The c.1278_1279del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 427 (NM_000162.5), adding 31 novel amino acids before encountering a stop codon (p.(Val427AlafsTer31)). 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 in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (internal lab contributor). In summary, the c.1278_1279del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting.