PSB and Decrypting Variants of Unknown Significance (VUS)

As a result of all this new structural information, the PSB is uniquely positioned to identify and triage novel coding variants that appear in clinical settings. As more patients have their genomes sequenced, variants of unknown significance (VUSs) are invariably identified, some of which may be implicated in the patients’ diagnosis. The PSB can evaluate these VUSs within the context of protein structure, possibly giving insight into the mechanism of disease (e.g. protein destabilization) or of treatment (e.g. disruption of drug target site).

The structural characterization of these VUSs is facilitated through the use of an inhouse, high-throughput analysis pipeline, VUStruct. VUStruct takes as input a list of VUSs (e.g. in the form of genomic coordinates), identify all that are missense coding variants, and then maps them onto all available structural models. VUStruct then applies a set of (user-customizable) analyses to interrogate patient variants using such structure driven methods as:

1. Proximity to other known pathogenic variants (PathProx)
2. Destabilizing effects on the protein structure
3. Evolutionary conservation of amino acids that are proximate in 3D space (COSMIS; github; web app)

As an example of how the structural approach taken by the PSB can be applied to clinical cases can be seen in a recent diagnosis within the UDN. The proband’s genome harbored a frameshift variant on one copy of fibroblast growth factor binding protein type 2 (FGFBP2). Viewed through the lens of structural biology, this VUS was predicted to ablate secondary structure in the protein (see Figure 1). This structural consequence would be predicted to inhibit the ability of FGFBP2 to bind fibroblast growth factor, thus providing a mechanistic model of pathogenicity.