The NM_000552.4(VWF):c.3437A>G (p.Tyr1146Cys) missense variant has been reported in at least 22 VWD type 2A patients. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/37812 alleles in the African/African-American population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.872, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of low VWF activity (VWF:RCo 16, VWF:CB 7) and VWF:Ag of 20 for a low VWF:CB activity/VWF:Ag ratio of 0.35, which is specific for VWD type 2A. (PP4; PMID: 24598842). Eight additional VWD 2A patients, with confirmatory lab values including very low VWF:RCo, low VWF:GPIb, and or low VWF activity/ VWF:Ag ratio, have been reported (PMIDs: 22871923, 16985174, 35452508, 20351307; PS4_VeryStrong). Multimer analysis in 293 cells expressing recombinant variant VWF showed reduced high molecular weight multimers indicating that this variant has a damaging effect on protein function (PMID: 20351307 Figure 3, PMID: 27533707 Figure 2; PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_VeryStrong, PS3, PM2_supporting, PP3, PP4.