Improving detection of monogenic diabetes through reanalysis of GCK variants of uncertain significance

This is the first VUS reclassification study in monogenic diabetes using gene-specific guidelines. Within the limits of this small study, we observed a high rate (50%) of VUS upgrades to a positive result, thereby confirming the utility of VUS reanalysis- particularly with biochemical phenotyping- in increasing the detection of monogenic diabetes. We recommend HbA1c, fasting blood glucose and either pancreatic autoantibody negativity or a small oral glucose tolerance test increment as a feasible minimum dataset to inform variant classification at the individual patient level, noting the ongoing work of the ClinGen Monogenic Diabetes Expert Panel in systematically reviewing GCK variants at the international level.