The c.1284_1362del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 429 (NM_000162.5), adding 159 novel amino acids before encountering a stop codon (p.(Arg429fsX159)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two individuals with diabetes/hyperglycemia consistent with GCK-MODY; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1284_1362del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting.