NM_000552.5:c.1728G>T is a missense variant in VWF that replaces methionine with isoleucine at position 576. The The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02820 (based on 1745/59454 alleles in the Admixed American population, with 41 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in the heterozygous state in at least 6 patients with a diagnosed blood disorder, with several exhibiting mild or moderate reduction of VWF:Ag (PMID: 17190853, PMID: 25780857, PMID: 33556167). However, diagnoses are not consistent and the variant is ineligible for consideration for PS4 due to its high frequency in the control population. The computational predictor REVEL gives a score of 0.038, 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.