ClinVar Genomic variation as it relates to human health

The c.1322C>G variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 OGTT increment < 3.0 mmol/L) (PP4_Moderate; PMID: 25665835). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ser441Trp has RAI=0.11, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 19884385). This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 27420379, 25665835, 19884385, 17573900, 16965331, 11508276, internal lab contributors). In summary, 1322C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3, PS4.

Published in vitro functional studies demonstrate greatly reduced enzyme activity compared to wildtype (Barbetti et al., 2009); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19884385, 25665835, 11508276, 17573900, 14517946, 28726111, 16965331)

The GCK c.1322C>G variant is predicted to result in the amino acid substitution p.Ser441Trp. This variant has been reported in multiple individuals with maturity-onset diabetes of the young (see for example, Figure 1, Massa et al. 2001. PubMed ID: 11508276; Table 1, Estalella et al. 2007. PubMed ID: 17573900; Oriola et al. 2015. PubMed ID: 25665835) and in multiple individuals with impaired fasting glucose (Figure 1, Barbetti et al. 2009. PubMed ID: 19884385; Table 2, Aloi et al. 2017. PubMed ID: 28726111). An in vitro experimental study shows this variant has greatly reduced enzyme activity compared to wildtype (Table 2, Barbetti et al. 2009. PubMed ID: 19884385). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.