Mapping genetic variations to three- dimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods

Genetic Variation in Bruton Tyrosine Kinase

X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by variations in the gene encoding for Bruton's tyrosine kinase (BTK). Patients with XLA have decreased numbers of mature B cells, lack all immunoglobulin isotypes, and therefore have susceptibility to severe bacterial infections. XLA-causing variations are collected into BTKbase freely available at http://structure.bmc.lu.se/idbase/BTKbase/. Details of the variations are provided at DNA, RNA, and protein levels, using standardized systematic names and a plain English description. In addition, clinical details from the patients are provided when available. BTKbase contains variation entries for 1362 patients from 1198 unrelated families altogether for 742 unique molecular events. The localization of the variations on the gene and protein for BTK can be analyzed by clicking sequences on web pages. The distribution of the variations in the five structural domains is approximately according to the length of the domains, except for the TH and SH3 domains. The most frequently affected sites are CpG dinucleotides. The majority of the amino acid substitutions are structural affecting protein fold or stability. Detailed statistics is provided highlighting variation types, affected domains, exons and introns, as well as structural consequences