ClinVar Genomic variation as it relates to human health

The VWF c.8084C>G; p.Pro2695Arg variant (rs76459136) is reported in the literature in several individuals affected with a bleeding disorder or low VWF levels (Lavin 2012, Manderstedt 2019) but also in a healthy control (Bellissimo 2012). Additionally, one affected individual with this variant also carried a missense variant in the F9 gene that likely explained their disease (Manderstedt 2019). The p.Pro2695Arg variant is found in the non-Finnish European population with an allele frequency of 0.05% (63/129160 alleles) in the Genome Aggregation Database. The proline at codon 2695 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.33). Due to limited information, the clinical significance of the p.Pro2695Arg variant is uncertain at this time. References: 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. Lavin M et al. Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. Blood. 2017 Nov 23;130(21):2344-2353. PMID: 28916584. Manderstedt E et al. Targeted re-sequencing of F8, F9 and VWF: Characterization of Ion Torrent data and clinical implications for mutation screening. PLoS One. 2019 Apr 26;14(4):e0216179. PMID: 31026269.

Observed in 2 individuals with low VWF levels (Lavin et al., 2017) and observed in an individual with a diagnosis of hemophilia B who also had a missense variant in the F9 gene (Manderstedt et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28916584, 31026269)

Variant summary: VWF c.8084C>G (p.Pro2695Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251448 control chromosomes (gnomAD). c.8084C>G has been reported in the literature in an individual with low VWF levels and one with hemophilia B without strong evidence of causality (Lavin_2017, Manderstedt_2019). 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: 28916584, 31026269). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

In the published literature, this variant has been reported in individuals with low VWF levels (PMID: 28916584 (2017)), and in an individual with hemophilia B (PMID: 31026269 (2019)). It is also reported in a healthy individual (PMID: 22197721 (2012)). The frequency of this variant in the general population, 0.00075 (38/50794 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.