ClinVar Genomic variation as it relates to human health

The c.1309_1310del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 437 (NM_000162.5), adding 21 novel amino acids before encountering a stop codon (p.(Thr437LeufsTer21)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and dominant family history of diabetes) (PP4_Moderate; internal lab contributors). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.1309_1310del 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, PM2_supporting, PP4_moderate, PS4_Moderate.