Distinguishing TSC-causing variants from those unlikely to cause TSC is essential for guiding patient care and further research. In collaboration with Dr. Mark Nellist (Erasmus MC, Rotterdam), we have shown that some missense changes and small in-frame deletions and insertions in the TSC1 and TSC2 genes, previously classified as variants of uncertain significance (VUS), have effects on TSC complex function [Hoogeveen-Westerveld et. al. Hum Mutat. 32:424-35 (2011); 33:476-9 (2012); 34:167-75 (2013); doi:10.1002/humu.23963 (2019)] and therefore, the likely cause of TSC in the patients. Refining the functional assay for clearer interpretation, as well as the continued testing of new and rare TSC variants are on-going.