The c.1331dup variant in the GCK gene causes a frameshift in the protein at codon 445 (NM_000162.5), adding 14 novel amino acids before encountering a stop codon (p.(Ser445GlnfsTer14)). While this variant, located in exon 10/10, is predicted to result in a premature stop codon that is predicted to escape nonsense mediated decay, it is a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a clinical picture consistent with monogenic diabetes; however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributor). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant segregated with disease with one informative meiosis in a family with MODY; however, this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, c.1331dup 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.