ClinVar Genomic variation as it relates to human health

Variant summary: GCK c.616A>C (p.Thr206Pro) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251436 control chromosomes. c.616A>C has been reported in the literature in multiple families affected with Monogenic Diabetes (Stern_2007, Gozalan_2012, Valentinova_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene, appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging.

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 206 of the GCK protein (p.Thr206Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity onset diabetes of the young (MODY) (PMID: 17937063, 21978167). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 129145). 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 expected to disrupt GCK protein function with a positive predictive value of 80%. This variant disrupts the p.Thr206 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11508276, 15928245, 16173921, 31216263). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.T206P variant (also known as c.616A>C), located in coding exon 6 of the GCK gene, results from an A to C substitution at nucleotide position 616. The threonine at codon 206 is replaced by proline, an amino acid with highly similar properties. This variant has been reported in multiple individuals with clinical phenotype consistent with maturity-onset diabetes of the young (Oron T et al. Pediatrics, 2011 Dec;128:e1614-7; Valentínová L et al. PLoS One, 2012 Apr;7:e34541; Alkorta-Aranburu G et al. Mol Genet Metab, 2014 Dec;113:315-320; Bennett JT et al. Mol Genet Metab, 2015 Mar;114:451-8; Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). In one cohort, this variant was identified in 6 unrelated Ashkenazi Jewish families with hyperglycemia, onset before age 25 years, negative autoantibodies, and at least one parent with a history of diabetes, suggestive of a possible founder mutation (Gozlan Y et al. Pediatr Diabetes, 2012 Sep;13:e14-21). In another study, this variant was shown to segregate with diabetes in 6 relatives with diabetes and was absent from 3 healthy relatives (Stern E et al. J Pediatr Endocrinol Metab, 2007 Aug;20:909-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Described as an ethnic-specific founder variant within the Ashkenazi-Jewish population (Baldacchino et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 29107759, 22065275, 17937063, 22101819, 31253563, 21978167)