NM_000552.5(VWF):c.4121G>A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 1374. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor computational predictor REVEL gives a score of 0.879, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Family M proband I.1 (PMID: 7734373) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a complete set of vWF multimers present but relative reduction of the larger multimers, low VWF:RCo/VWF:Ag ratio (<0.4), and VWF:RCo <3-10 IU/dl (PP4). Additional consistent phenotypes included FVIII activity consistent with VWF antigen. This variant has been reported in >8 additional probands with consistent laboratory phenotypes (PS4_VeryStrong; PMIDs: 7620154, 9031470, 11154147, 7734373, 38315875, 28083987, 28536718). The variant has been reported to segregate with VWD type [2A/2M] through at least 2 affected meioses in at least 2 families (PP1_Moderate; PMID: 7734373, PMID: 7620154). A platelet binding assay in COS-7 cells expressing the recombinant VWF variant showed decreased binding indicating that this variant has a damaging effect on protein function relative to the rVWF wild-type control (PMID: 10845912, PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS4_VeryStrong, PM2_supporting, PP1_Moderate, PP3, PP4. Recent analysis (PMID: 38315875) reports that patients with R1374H have severely reduced VWF:GPIbR/VWF:Ag and a modest decrease in VWF:CB/VWF:Ag ratios. This can be explained by 2 defects, (1) a reduced VWF A1 domain binding to GPIb and (2) an altered VWF multimeric pattern in which patients showed a slightly diminished proportion of HMWM and little increase of low and intermediate multimers. They hypothesize that the slight reduction of HMWM (characteristic of type 2A) is primarily responsible for marginally reduced VWF:CB/VWF:Ag ratio, whereas the markedly reduced VWF:GPIbR/VWF:Ag ratio is mainly because of a type 2M defect (diminished binding of A1-GPIb) and propose a subtype designation of 2M/2A for this variant.