ClinVar Genomic variation as it relates to human health

The c.601G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 201 (p.(Ala201Ser)) 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 0.929, 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 four unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in one family (PP1_Strong; internal lab contributors). In summary, c.605T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PS4_Moderate, PP1_Strong, PP4_Moderate.

PM2, PP3, PM1, PP5

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala201 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 25555642), 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: 198050). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 19790256, 25555642, 33046911; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 201 of the GCK protein (p.Ala201Ser).

The p.A201S variant (also known as c.601G>T), located in coding exon 6 of the GCK gene, results from a G to T substitution at nucleotide position 601. The alanine at codon 201 is replaced by serine, an amino acid with similar properties. This variant has been reported in association with maturity-onset diabetes of the young (MODY) (Osbak KK et al. Hum Mutat, 2009 Nov;30:1512-26). It was also reported in four individuals with suspicion of MODY and nine relatives; however, additional information was not provided (Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Classified pathogenic by the ClinGen Monogenic Diabetes Expert Panel (ClinVar SCV004697928.1); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 33046911, 25555642, 36257325, 19790256)