An enhanced workflow for variant interpretation in UniProtKB/Swiss-Prot improves consistency and reuse in ClinVar

M L Famiglietti,S Poux,I Xenarios,A Bridge,L Breuza,N Redaschi,A Estreicher

doi:10.1093/database/baz040

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.

Highlights

The use of patient sequence data in personalized medicine requires reference knowledge on the functional impact and role of genetic variants in human disease
We find that existing variant annotations that are common to the two resources are highly consistent and that consistency is further improved by re-curation of UniProtKB/Swiss-Prot variants using ClinGen tools for variant interpretation and guidelines provided by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP, abbreviated here as ACMG) [2]
We reasoned that comparison of variants from UniProtKB/Swiss-Prot with the set of ClinVar 2-star records—where multiple submitters agree on the interpretation of clinical significance, but which lack validation by expert panels—is likely to provide an interpretable upper-bound estimate of the level of disagreement between UniProtKB/Swiss-Prot and ClinVar

Summary

Introduction

The use of patient sequence data in personalized medicine requires reference knowledge on the functional impact and role of genetic variants in human disease. The development of standardized guidelines for variant interpretation [1,2,3,4] and freely available repositories of variant data such as ClinVar [5], as well as efforts by ClinVar and ClinGen to standardize the annotation of clinical variants [6, 7] (see https://www.clinicalgenome.org/about/about-the-clingenand-clinvar-partnership/), has been a major factor in improving the availability of reliable, high-quality genetic variant data for researchers and clinicians Resources such as ExAC and gnomAD provide variant frequency data for large population data sets that create a framework to reevaluate earlier pedigree studies and are another important part of ongoing efforts to standardize and improve variant interpretation [8]. The additional context provided by curated information on protein function, subcellular location, interactions and sequence features, such as protein domains, active sites and post-translational modifications, can help to inform the analysis of the role of sequence variants in disease

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Results

Conclusion