Current status and future perspectives of the evaluation of missense variants by using three-dimensional structures of proteins.

Abstract

Changes in the amino acid sequences of proteins may cause changes in molecular function, resulting in phenotypic variations among species and individuals. Such amino acid changes occur naturally due to mutations in the genome sequence of an organism and can be inherited. Recent advances in genome sequencing technologies have enabled us to sequence the genomes of millions of humans, as performed by various large-scale projects such as the Genome Aggregation Database (gnomAD) [1], Trans-Omics for Precision Medicine (TOPMed) [2], and UK Biobank [3]. Further, it has enabled us to accumulate known pathogenic variants in databases such as ClinVar [4], Human Genome Mutation Database (HGMD) [5] and Catalogue of Somatic Mutations in Cancer (COSMIC) [6]. These studies