NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys) missense variant is predicted to cause substitution of arginine by cysteine at amino acid 1308. This variant has been reported in at least 30 probands, of which at least 19 reported sufficient phenotypic information to confirm type 2B VWD. (PS4; PMIDs: 18805962, 22077376, 1419803, 2010538, 16246252). Patient 9 of PMID: 2010538, has sufficient information to meet PP4_moerate: lacked HMWM in plasma and had a moderately heightened RIPA (0.6–0.7), as well as low VWF:RCo/VWF:Ag ratio (<0.45), with Platelet-type VWD excluded by mixing experiments to confirm that the defect was in the patient plasma and not in the patient platelets. The variant has been reported to segregate with VWD type 2B through at least 2 affected meioses from 1 family (PP1; PMID: 2010538). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VWD type 2B (PPS2_supporting; PMID: 2010538). This variant is absent from gnomAD v4.1 (PM2_Supporting). GP1bα binding assay in COS-7 cells expressing recombinant VWF, variant alone or together with WT, showed increased binding at low doses of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID: 16246252) (PS3). Similar results have been reported in multiple studies (PMIDs: 26345337, 8630394). The computational predictor REVEL gives a score of 0.673, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3_supporting, PS4_VeryStrong, PM2_supporting, PS2_supporting, PP1, PP3, PP4_moderate.