ClinVar Genomic variation as it relates to human health

The c.1160C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 387 (p. (Ala387Val)) of NM_000162.5. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to no copies in the European non-Finnish subpopulation and one copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (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 located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein's function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.871 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1159G>A p.(Ala387Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala387Glu has a greater Grantham distance (PM5). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 34421822, Internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 34421822). This variant segregated with hyperglycemia, with five informative meioses in three families (PP1_Strong; PMID: 34421822, Internal lab contributor). In summary, c.1160C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5, PS4_Moderate, PP4_Moderate.

The A387V variant has been previously published in association with GCK-MODY (Thomson et al., 2003; Pruhova et al., 2010). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A387V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species within the hexokinase domain; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (A387E/T) and in nearby residues (G385R/W/V, L386V, G388D) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded

The p.Ala387Val variant in GCK has been reported in at least 4 individuals (including 1 Czech individual, 1 Asian individual, and 1 Caucasian individual from the UK) with Monogenic Diabetes (PMID: 14517956, 19790256, 20337973), and has been identified in 0.003400% (1/29414) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193921338). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability/reduced penetrance. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36182). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Ala387Val have been reported in association with disease in ClinVar, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (Variation ID: 435300, 36180, 36179). Two additional variants (p.Ala387Glu and p.Ala387Thr) causing a different amino acid change at the same position have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 19790256; Variation ID: 36181). The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP2, PP3, PS4_Supporting, PM1_Supporting (Richards 2015).

Converted during submission to Likely pathogenic.

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ala387 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 23771925), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 36182). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 14517956, 20337973, 34221822, 34421822). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 387 of the GCK protein (p.Ala387Val).