Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts

Abstract

While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze variant information with high throughput. Clinotator is a fast and lightweight tool to extract important aspects of criteria-based clinical assertions; it uses that information to generate several metrics to assess the strength and consistency of the evidence supporting the variant clinical significance. Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation. This can be accomplished in batches: either lists of Variation IDs or dbSNP rsIDs, or with vcf files that are additionally annotated. Using sample sets ranging from 15,000–50,000 variants, we slice out problem variants in minutes without extensive computational effort (using only a personal computer) and corroborate recently reported trends of discordance hiding amongst the curated masses. With the rapidly growing body of variant evidence, most submitters and researchers have limited resources to devote to variant curation. Clinotator provides efficient, systematic prioritization of discordant variants in need of reclassification. The hope is that this tool can inform ClinVar curation and encourage submitters to keep their clinical assertions current by focusing their efforts. Additionally, researchers can utilize new metrics to analyze variants of interest in pursuit of new insights into pathogenicity.

Scaling resolution of variant classification differences in ClinVar between 41 clinical laboratories through an outlier approach

“…These types of submissions are more likely to be outlier classifications compared to clinical testing classifications (Yang et al, 2017). Additionally, new tools have been developed for ClinVar submitters and users to identify custom sets of conflicting classification, such as by submitter or by level of conflict (Henrie et al 2018; Butler et al 2018).…”

Simple ClinVar: an interactive web server to explore and retrieve gene and disease variants aggregated in ClinVar database

“…Without prior bioinformatics knowledge, the evaluation of the entire database, filtering, or parsing of multiple high confidence variants becomes extremely difficult. To address this issue, several platforms have been developed such as ClinVar Miner (7), ClinVar data parsing (8) and Clinotator (9) that offer parsing solutions limited to the extraction of ClinVar variants and the development of additional interpretation metrics (9) that can be still overwhelming for non-expert users. In this regard, ClinVar filtering is often not enough to facilitate user analysis.…”