ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.683C>T (p.Thr228Met) (rs80356655)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000498792 SCV000613451 pathogenic not provided 2013-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000498792 SCV000589594 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing The T228M variant has been published previously in association with MODY, including a confirmed de novo occurrence (Stanik et al., 2014; Costantini et al., 2015). The variant has also been observed in the homozygous state in patients with neonatal diabetes mellitus (Stoffel et al., 1992; Njølstad et al., 2001). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T228M is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the substrate-binding site that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown T228M nearly eliminates the catalytic activity of the GCK protein (Njølstad et al., 2001; Molnes et al., 2011). Missense variants in the same residue (T228A/K/R) and in nearby residues (I225F/M, V226E/M, G227R/S/C, G229V/D, N231H/S) 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. In summary, we consider this variant to be pathogenic.
GeneReviews RCV000020167 SCV000040495 pathologic Maturity-onset diabetes of the young, type 2 2011-07-05 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000020167 SCV000037786 pathogenic Maturity-onset diabetes of the young, type 2 1992-08-15 no assertion criteria provided literature only
OMIM RCV000030923 SCV000037795 pathogenic Permanent neonatal diabetes mellitus 2001-05-24 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.