ClinVar Genomic variation as it relates to human health

The c.1398A>G variant in the glucokinase gene, GCK, causes an amino acid change at the stop codon of the final exon (10/10), resulting in the addition of 144 amino acids at the end of the protein (p.(Ter466ArgextTer144)). 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 an individual with a clinical history consistent with GCK-hyperglycemia, but there was insufficient clinical data to evaluate for PP4 (internal lab contributors). Taken together, this evidence supports the classification of this variant as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: PVS1, PM2_Supporting. (Specification version 1.2.0, approved 6/7/23)