Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000419860 | SCV000521046 | likely pathogenic | not provided | 2016-08-02 | criteria provided, single submitter | clinical testing | The M235V variant has been published previously in association with MODY (GarcÃa-Herrero et al., 2007). It 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. M235V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and functional studies have shown M235V results in lowered protein stability at higher temperatures as well as lowered catalytic activity compared to wild type (GarcÃa-Herrero et al., 2007). Missense variants in the same codon (M235T/R) and in nearby residues (A232D, C233R/S, Y234H, E236K/A, E237K) 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. |
| Invitae | RCV000419860 | SCV002246004 | pathogenic | not provided | 2023-07-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 17186219). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 235 of the GCK protein (p.Met235Val). 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 (PMID: 17186219, 24323243). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 381599). 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. |