ClinVar Genomic variation as it relates to human health

The c.1398A>T variant in the glucokinase gene, GCK, causes a change from the stop codon to cysteine in the final exon (10/10), resulting in the addition of 144 amino acids at the end of the protein (p.(Ter466CysextTer144)). 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 was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L and negative antibodies) (PP4_Moderate; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with hyperglycemia with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1398A>T 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 6/7/2023): PVS1, PP4_Moderate, PM2_Supporting.