NM_000552.5:c.391G>A is a missense variant in VWF that replaces glycine with serine at position 131. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02093 (based on 1636/75004 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). This variant has been reported in the heterozygous state in at least 5 reported healthy control individuals with no bleeding history and normal lab values (PMID: 22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. The computational predictor REVEL gives a score of 0.141, 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 a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4.