Journal
HUMAN GENETICS
Volume 137, Issue 9, Pages 665-678Publisher
SPRINGER
DOI: 10.1007/s00439-018-1916-x
Keywords
Deep mutational scanning; MAVE; Variant effect; VUS; Variants of uncertain significance
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Funding
- One Brave Idea Initiative
- National Human Genome Research Institute of the National Institutes of Health (NIH/NHGRI) Center of Excellence in Genomic Science (CEGS) Initiative [HG004233]
- Canadian Excellence Research Chairs (CERC) Program
- Ontario Ministry of Research and Innovation (MRI)
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Given the constantly improving cost and speed of genome sequencing, it is reasonable to expect that personal genomes will soon be known for many millions of humans. This stands in stark contrast with our limited ability to interpret the sequence variants which we find. Although it is, perhaps, easiest to interpret variants in coding regions, knowledge of functional impact is unknown for the vast majority of missense variants. While many computational approaches can predict the impact of coding variants, they are given a little weight in the current guidelines for interpreting clinical variants. Laboratory assays produce comparatively more trustworthy results, but until recently did not scale to the space of all possible mutations. The development of deep mutational scanning and other multiplexed assays of variant effect has now brought feasibility of this endeavour within view. Here, we review progress in this field over the last decade, break down the different approaches into their components, and compare methodological differences.
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