ClinVar Genomic variation as it relates to human health

The c.1270C>T variant in the glucokinase gene, GCK, causes an amino acid change of histidine to tyrosine at codon 424 (p.(His424Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.897, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 1709730, PMIDs: 27726111, 22035297, 31595705 internal lab contributors), including 3 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% as well as OGTT increment < 3 mmol/L and/or negative antibodies in untreated pediatric case) (PP4_Moderate; PMIDs: 19410318, 28726111, internal lab contributors). This variant segregated with hyperglycemia, with 4 informative meioses in 1 family (PP1_Moderate; PMIDs: 22035297). In summary, c.1270C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP1_Moderate, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

The GCK c.1270C>T variant is predicted to result in the amino acid substitution p.His424Tyr. This variant has been reported in several individuals with Maturity Onset Diabetes of the Young (MODY) (Solera et al 2009. PubMed ID: 19410318; Borowiec et al. 2012. PubMed ID: 22035297; Tracz et al. 2014. PubMed ID: 24918535). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant summary: GCK c.1270C>T (p.His424Tyr) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 244634 control chromosomes. c.1270C>T has been reported in the literature in individuals affected with clinical features of GCK-associated Monogenic Diabetes (example, Soldera_2009, Borowiec_2012, Aloi_2017, Campos Franco_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28726111, 22035297, 35472491, 19410318). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.