Abstract

Personalized genomic medicine depends on integrated analyses that combine genetic and phenotypic data from individual patients with reference knowledge of the functional and clinical significance of sequence variants. Sources of this reference knowledge include the ClinVar repository of human genetic variants, a community resource that accepts submissions from external groups, and UniProtKB/Swiss-Prot, an expert-curated resource of protein sequences and functional annotation. UniProtKB/Swiss-Prot provides knowledge on the functional impact and clinical significance of over 30 000 human protein-coding sequence variants, curated from peer-reviewed literature reports. Here we present a pilot study that lays the groundwork for the integration of curated knowledge of protein sequence variation from UniProtKB/Swiss-Prot with ClinVar. We show that existing interpretations of variant pathogenicity in UniProtKB/Swiss-Prot and ClinVar are highly concordant, with 88% of variants that are common to the two resources having interpretations of clinical significance that agree. Re-curation of a subset of UniProtKB/Swiss-Prot variants according to American College of Medical Genetics and Genomics (ACMG) guidelines using ClinGen tools further increases this level of agreement, mainly due to the reclassification of supposedly pathogenic variants as benign, based on newly available population frequency data. We have now incorporated ACMG guidelines and ClinGen tools into the UniProt Knowledgebase (UniProtKB) curation workflow and routinely submit variant data from UniProtKB/Swiss-Prot to ClinVar. These efforts will increase the usability and utilization of UniProtKB variant data and will facilitate the continuing (re-)evaluation of clinical variant interpretations as data sets and knowledge evolve.

Keywords

UniProtWorkflowComputer scienceConsistency (knowledge bases)Computational biologyBioinformaticsInformation retrievalBiologyGeneticsDatabaseArtificial intelligence

Affiliated Institutions

Related Publications

Publication Info

Year
2019
Type
article
Volume
2019
Citations
22
Access
Closed

External Links

View on DOI.org

Social Impact

Altmetric
PlumX Metrics

Social media, news, blog, policy document mentions

Citation Metrics

22
OpenAlex

Cite This

Maria Livia Famiglietti, Anne Estreicher, Lionel Breuza et al. (2019). An enhanced workflow for variant interpretation in UniProtKB/Swiss-Prot improves consistency and reuse in ClinVar. Database , 2019 . https://doi.org/10.1093/database/baz040

Identifiers

DOI
10.1093/database/baz040