NM_000552.5(VWF):c.3692A>C is a missense variant encoding a substitution of asparagine by threonine at position 1231. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID: 8134377, PMID: 17190853, PMID: 31064749, PMID: 16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID: 8134377, PMID: 2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least two control individuals (PMID: 22197721). REVEL gives a score of 0.069, 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. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID: 16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01138 (based on 900/74802 alleles in the African/African-American population, including 7 homozygotes), which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4.