The c.1148del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 383 (NM_000162.5), adding 19 novel amino acids before encountering a stop codon (p. (Ser383Trpfs*19)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), but has been detected in two unrelated probands with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (Internal lab contributors). One proband, along with his sister, was diagnosed with neonatal diabetes; they have this variant in the homozygous state (PP4, PM3_Supporting; internal lab contributor). In summary, c.1148del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v 1.3.0; approved 8/11/2023): PVS1, PM2_Supporting, PM3_Supporting, PP4.