Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts

Area of Science:

• Genomics
• Bioinformatics
• Clinical Genetics

Background:

• ClinVar is a vital resource for clinical variant interpretation but presents a steep learning curve due to its complex data structure.
• High-throughput analysis of variant information is challenging due to the depth and breadth of data available in ClinVar.

Purpose of the Study:

• To develop a fast and lightweight tool, Clinotator, for extracting and analyzing clinical assertions from ClinVar.
• To generate metrics for assessing the strength and consistency of evidence supporting variant clinical significance.
• To facilitate efficient prioritization of discordant variants for reclassification and improve ClinVar data quality.

Main Methods:

• Clinotator extracts key information from criteria-based clinical assertions in ClinVar.
• Assertions are weighted by significance type, submission date, and submitter expertise to filter outdated or incomplete data.
• The tool processes batch inputs including Variation IDs, dbSNP rsIDs, or annotated VCF files.

Main Results:

• Clinotator efficiently identifies problematic variants within minutes on a personal computer, even with large datasets (15,000-50,000 variants).
• The tool corroborates existing trends of discordance within curated variant data.
• New metrics are generated to aid researchers in analyzing variants and gaining insights into pathogenicity.

Conclusions:

• Clinotator offers an efficient and systematic method for prioritizing variants that require reclassification, addressing resource limitations in variant curation.
• The tool can inform ClinVar curation efforts and encourage submitters to maintain current clinical assertions.
• Researchers can leverage Clinotator's metrics for novel variant analysis and pathogenicity investigations.