The NM_000552.5:c.2546G>A variant encodes a missense substitution of cysteine by tyrosine at codon 849 in VWF. The variant has been reported in at least 1 patient displaying excessive mucocutaneous bleeding as well as laboratory phenotypes of low activity/VWF:Ag ratio and loss of high molecular weight multimers, which together are specific for VWD type 2A. (PP4, PMID: 19422453, PMID: 35452508). The patient had three heterozygous missense mutations (R202W, C849Y, and R1583Q) in the VWF gene. R1583Q is classified Likely Benign by the VWD VCEP and R202W (ClinVar 619940 VUS) is also considered a VUS at this time. The variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.579, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. However, the splicing predictor SpliceAI gives a delta score of 0.72 for donor loss (PP3), which has been functionally confirmed to result in an aberrant splicing product in an affected individual (Figure 3, PMID: 19422453). Multimerization assay performed with the p.Cys849Tyr recombinant mutant and a wild-type control vWF expressed by COS-7 cells showed absence of higher-MW multimers, indicating that this variant has a damaging effect on protein function consistent with the multimerization defect observed in the proband (PS3, PMID: 19422453). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP3, PP4.