Incidence of severe events by class of variant. Cumulative incidence of the first severe disease-related event comparing those with class I variants (missense variant in exons 1+2 or the c.559+5G>A intronic variant) with class II variants (all other variants) including all patients (left) or excluding patients with VUS (right): any severe event (A-B), severe bleeding (C-D), severe infection (E-F), autoimmunity (G-H), and malignancy (I,J). Variants classified as “likely benign” or “benign” were excluded from this analysis.