NM_000552.5(VWF):c.2220G>A is a missense variant that replaces methionine with isoleucine at position 740. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1791 (based on 13626/75022 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). This variant has been observed in multiple VWD Type 2M probands in cis with the NM_000552.5(VWF):c.3614G>A (p.Arg1205His) variant, with the phase of the variants confirmed by family segregation analysis (PMID: 10959712). This second variant has been classified Pathogenic for VWD Type 2M by the ClinGen VWD VCEP (BP2). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4.