ClinVar Genomic variation as it relates to human health

The VWF c.6937C>T; p.Arg2313Cys variant (rs184921605) is reported in the literature in an individual with low von Willebrand factor (Boylan 2015). This variant is also reported in ClinVar (Variation ID: 993252). This variant is found in the Latino population with an allele frequency of 0.6 % (234/ 35,440 alleles, including 0 homozygotes) in the Genome Aggregation Database. The arginine at codon 2313 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.29). Due to limited information, the clinical significance of the p.Arg2313Cys variant is uncertain at this time.

In the published literature, the variant has been reported in an individual with hemophilia A (HA) who exhibited low plasma VWF antigen (VWF:Ag) and Factor VIII (FVIII) binding capacities (PMID: 25780857 (2015)). The frequency of this variant in the general population, 0.003 (75/24960 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 benign. Taking into account the available information, we are unable to determine the clinical significance of this variant.

Variant summary: VWF c.6937C>T (p.Arg2313Cys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 251482 control chromosomes, predominantly at a frequency of 0.0066 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in VWF causing Von Willebrand Disease phenotype. c.6937C>T has been reported in the literature in at least one individual affected with Von Willebrand Disease (Boylan_2015). These report(s) 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 publication have been ascertained in the context of this evaluation (PMID: 25780857). ClinVar contains an entry for this variant (Variation ID: 993252). Based on the evidence outlined above, the variant was classified as likely benign.

PM1

The VWF c.6937C>T variant is predicted to result in the amino acid substitution p.Arg2313Cys. This variant has been reported in an individual with Von Willebrand disease (Boylan et al. 2015. PubMed ID: 25780857). This variant is reported in 0.66% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.