ClinVar Genomic variation as it relates to human health

The p.Ser262Pro variant in GCK has been reported in at least 3 individuals with suspicion for MODY and segregated with disease in at least 3 affected members of two families (Cao 2002, Sagen 2006, GeneDx personal communication). It has also been identified in 1/128844 European chromosomes by gnomAD (http://gnomad.broad institute.org) and has been reported as likely pathogenic in ClinVar (Variation ID 36258). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. However, multiple in vitro functional studies suggest that this variant impacts protein function (Sag en 2006, Zelent 2011, Fenner 2011, Negahdar 2012, George 2014). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Ser262Pro variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PS4_Supporting.

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected the stability and activity of the protein (PMID: 22820548, 22028181, 21921030).

The p.S263P variant (also known as c.787T>C), located in coding exon 7 of the GCK gene, results from a T to C substitution at nucleotide position 787. The serine at codon 263 is replaced by proline, an amino acid with similar properties. This variant was identified in two maturity-onset diabetes of the young families (Cao H et al. Hum. Mutat., 2002 Dec;20:478-9; Sagen JV et al. Diabetes, 2006 Jun;55:1713-22). When stably over expressed in HEK293 cells and MIN6 cells, this variant generated a misfolded protein with an increased rate of degradation and a propensity to self-associate and form dimers and aggregates (Negahdar M et al. Biochim. Biophys. Acta, 2012 Nov;1822:1705-15). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The c.787T>C variant in codon 263 (exon 7) of the glucokinase gene, GCK, results in the substitution of Serine to a Proline. The c.787T>C was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported to segregate with diabetes in a family whose clinical picture is consistent with Maturity-Onset Diabetes of the Young (MODY) (12442280). Functional analyses of this variant have demonstrated thermal instability, protein misfolding and aberrant dimerization (22820548;16731834). Additionally, multiple lines of computational evidence (SIFT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PS3, PM2, PP1, PP3

Converted during submission to Likely pathogenic.

The heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the exon 7 of GCK gene has been reported in multiple patients with hyperglycemia and found to be co-segregated with disease phenotype [PMID: 22820548, 16731834, 32074423] and was reported as pathogenic in a cohort study involving hypertriglyceridemia and familial hypercholesterolemia patients [PMID: 32041611]. In vitro functional studies demonstrated that p. Ser263Pro variant leads to protein misfolding, thermal instability and aberrant dimerization [PMID:22820548,16731834]. The variant has 0.000006570 allele frequency in the gnomAD(v3) database (1 out of 152218 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The identified variant has been reported in the ClinVar database as a Likely Pathogenic [Variation ID: 36258]. The variant affects a moderately conserved residue in the large hexokinase domain of the GCK protein [PMID: 31638168] and is predicted deleterious by multiple in silico tools (CADD score = 22.7, REVEL score = 0.689). Based on the available evidence, the heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the GCK gene is classified as ‘Likely Pathogenic’.

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 263 of the GCK protein (p.Ser263Pro). This variant is present in population databases (rs193922331, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 12442280, 25306193, 25555642, 32074423; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36258). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 21921030, 22028181, 22820548). For these reasons, this variant has been classified as Pathogenic.

Reported in association with MODY in published literature (PMID: 25306193, 32074423, 12442280, 25555642); however, patient-specific clinical information not provided; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12442280, 15305805, 32041611, 21831042, 22820548, 21921030, 22028181, 16731834, 32074423, 25555642, 36257325, 25306193)

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.787T>C, in exon 7 that results in an amino acid change, p.Ser263Pro. The p.Ser263Pro change affects a poorly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser263Pro substitution. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0032% % (dbSNP rs193922331). This sequence change has been previously reported in patients with GCK-related hyperglycemia (PMIDs: 12442280, 16731834). Functional studies have also demonstrated that p.Ser263ro sequence change results in reduced protein misfolding and aberrant dimerization (PMIDs: 22820548, 16731834). These collective evidences indicate that this sequence change is the likely pathogenic.

The GCK c.787T>C variant is predicted to result in the amino acid substitution p.Ser263Pro. This variant has been repeatedly reported to be pathogenic for maturity-onset diabetes of the young (MODY) due to reduced thermal stability (S263P at Cao et al. 2002. PubMed ID: 12442280; McKinney JL et al 2004. PubMed ID: 15305805; Sagen JV et al 2006. PubMed ID: 16731834; García-Herrero CM et al 2006. PubMed ID: 17186219; Zelent B et al 2011. PubMed ID: 21831042; Negahdar et al. 2012. PubMed ID: 22820548; Bennett JT et al 2014. PubMed ID: 25555642). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.