ClinVar Genomic variation as it relates to human health

Observed in the homozygous state in an individual with von Willebrand disease who had an additional homozygous VWF variant in cis (Corrales et al., 2010); Observed in individuals with von Willebrand disease who have a second VWF variant, however it is unknown if these variants are in cis or trans (Sadler et al., 2021); 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: 26986123, 28971901, 31064749, 27532107, 33556167, 20801902)

In the published literature, this variant has been reported in individuals with low VWF and/or Type 1 von Willebrand disease (VWD) co-occurring with another likely pathogenic/pathogenic variant in the VWF gene (PMID: 33556167 (2021)). It has also been reported in an individual with Type 3 VWD in the homozygous state with a homozygous canonical splice variant (PMID: 20801902 (2010), 21251206 (2011), 28971901 (2017)). This variant has also been reported individuals with Type 1, Type 1H, and Type 2A VWD (PMID: 26986123 (2016), 27532107 (2016), 28971901 (2017)), as well as in an individual with a bleeding, thrombotic, or platelet disorder (PMID: 31064749 (2019)). The frequency of this variant in the general population, 0.0015 (4/2642 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: VWF c.1625C>G (p.Ala542Gly) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 250426 control chromosomes (gnomAD). c.1625C>G has been reported in the literature in individuals affected with Von Willebrand Disease (Corrales_2010, Casonato_2016, Veyradier_2016, Sadler_2021, Borras_2017). One patient was reported as putatively compound heterozygous with a pathogenic variant, although other patients were found to have a likely pathogenic variant in cis or without the phase indicated. These data do not allow any conclusion about variant significance. 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: 20801902, 27532107, 26986123, 33556167, 28971901, 21251206, 31064749). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classified it as uncertain significance (n=4), or pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

The VWF c.1625C>G variant is predicted to result in the amino acid substitution p.Ala542Gly. This variant has been reported in patients with von Willebrand disease, but has always been reported in a cis configuration with a splice site variant c.533-2A>G making it unclear whether the missense variant p.Ala542Gly is actually a cause of disease (see Corrales et al. 2010. PubMed ID: 20801902; http://www.hemobase.com/vwf/VWF_Database/Mutations/Mutations.html). This variant has also been reported in studies of VWD patients, but it is unclear whether it is a cause of disease within the studied cohort (Veyradier et al. 2016. PubMed ID: 26986123; Table S2 - Sadler et al. 2021. PubMed ID: 33556167). Additionally, the c.1625C>G (p.Ala542Gly) variant was observed in a cohort of individuals with bleeding, thrombotic and platelet disorders, and reported as likely pathogenic (TGP0672, Supplementary Table 3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.14% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6167119-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.