ClinVar

Description

Variant summary: VWF c.7988G>C (p.Arg2663Pro) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 251232 control chromosomes in gnomAD v2, and 4 homozygotes were reported in gnomAD v4. dataset. c.7988G>C has been reported in the literature in individuals affected with Von Willebrand Disease and coagulation disease, either at a compound heterozygous or a heterozygous status (Goodeve_2007, Downes_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. Co-occurrences with other pathogenic variant(s) have been reported in a patient with Haemophilia (F8 c.6320G>A, Gly2107Ser), providing supporting evidence for a benign role (Borras_2022). 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: 34708896, 31064749, 16985174). ClinVar contains an entry for this variant (Variation ID: 372760). Based on the evidence outlined above, the variant was classified as uncertain significance.