ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population, 0.015 (380/24964 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been briefly reported in an individual with venous thromboembolism (PMID: 31352677 (2019)). In addition, this variant has been reported in healthy controls (PMID: 34662354 (2021)) and in individuals affected with type 2M VWD (PMID: 22197721 (2012), 16321553 (2006)). Based on the available information, we are unable to determine the clinical significance of this variant.

The VWF c.3101_3103del; p.Thr1034del variant (rs368366214) is reported in the literature in individuals affected with von Willebrand disease (VWD), but also in healthy controls (Baronciani 2021, Bellissimo 2012, Kakela 2006). This variant has been observed in the homozygous or compound heterozygous state in several individuals with type 3 VWD (Baronciani 2021), but one heterozygous individual with this variant was reported with VWD type 2M (Kakela 2006). This variant is found in the African population with an allele frequency of 1.5% (380/24964 alleles, including three homozygotes) in the Genome Aggregation Database. This variant deletes a single threonine residue, leaving the rest of the protein in-frame. Due to limited and conflicting information, the clinical significance of the p.Thr1034del variant is uncertain at this time. References: Baronciani L et al. Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS. Blood Adv. 2021 Aug 10;5(15):2987-3001. PMID: 34351388. Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Kakela JK et al. Genetic mutations in von Willebrand disease identified by DHPLC and DNA sequence analysis. Mol Genet Metab. 2006 Mar;87(3):262-71. PMID: 16321553.

BS1, BS2, PM4

Variant summary: VWF c.3101_3103delCCA (p.Thr1034del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.0012 in 251670 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. c.3101_3103delCCA has been reported in the literature in individuals affected with bleeding disorders including Von Willebrand Disease as well as unaffected controls (Baz_2021, Bellissimo_2012, Kakela_2006, Manderstedt_2019, Sadler_2021). These reports do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16321553, 22197721, 34272389, 33556167, 31352677). ClinVar contains an entry for this variant (Variation ID: 802812). Based on the evidence outlined above, the variant was classified as uncertain significance.

VWF: BS1, BS2