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 Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation.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.

Keywords: ClinVar; benign; clinical variant; pathogenic; pathogenicity; variant interpretation; variant reclassification; variation.

Figure 1.. Clinotator raw score (CTRS) distribution of two-star ClinVar variants.

( A) All two-star variants, plotted according to CTRS, and colored based on the seven ClinVar clinical significance designations: Benign (B), Benign/Likely benign (BLB), Likely benign (LB), Uncertain Significance (US), Likely pathogenic (LP) Pathogenic/Likely pathogenic (PLP) and Pathogenic (P). ( B) Prediction intervals (PI) for the five primary Mendelian clinical significances (B, LB, US, LP and P). Intervals plotted by CTRS value, using five different interval confidences (vertical axis). The optimal confidence interval for each clinical significance is marked with an asterisk. ( C) All two-star variants plotted according to Clinotator Raw Score, and colored based on the seven Clinotator predicted significance ranges (B, BLB, LB, US, LP, PLP and P) after calibration with prediction intervals. Dashed lines denote prediction interval boundaries from ( B).

Figure 2.. Clinotator reclassification recommendations (CTRR).

( A) A schematic of the CTRR scoring workflow. ClinVar Clinical Significance (CVCS) is used as a starting point, and each significance passed to arrive at the Clinotator Predicted Significance (CTPS) counts as a point. Transitioning a significance family boundary adds an extra point (moving from Uncertain Significance (US) to either Likely benign (LB) or Likely pathogenic (LP)). Benign (B), Benign/Likely benign (BLB), Pathogenic/Likely pathogenic (PLP), and Pathogenic (P). ( B) A heat map of variant counts for two-star variants (per ClinVar’s review status star ratings), with each CVCS and CTPS combination. Darker squares correspond to higher numbers of variants. Blue represents a CTRR of zero, light blue a CTRR of one, orange a CTRR of two and red a CTRR of three. ( C) A heat map of variant counts for three-star variants using the same layout as ( B).

Figure 3.. Number of clinical assertions (CVNA) given a Clinotator raw score (CTRS).

( A) All two-star variants plotted by CVNA and CTRS. Values are colored according to their Clinotator reclassification recommendation (CTRR): blue represents a score of zero, light blue a score of one, yellow a score of two and red a score of three. ( B) All three-star uncertain significance variants, plotted in the same manner and coloring scheme. ( C) All conflicting interpretations of pathogenicity variants.

Figure 4.. Conflicting interpretation of pathogenicity (CI) variants by number of clinical assertions (CVNA).

CI variants with a Clinotator reclassification recommendation (CTRR) of three, counted by CVNA and colored by Clinotator predicted significance (CTPS). Blue represents Benign (B), light blue represents Benign/Likely benign (BLB), orange represents Pathogenic/Likely pathogenic (PLP) and red is Pathogenic (P). The asterisk denotes the column of 16 variants examined in Table 4.