Documentation / Reference Databases / ClinVar
ClinVar
ClinVar is a public archive of clinical significance assertions for genetic variants, maintained by the National Center for Biotechnology Information (NCBI). It aggregates submissions from clinical laboratories, research groups, and expert panels worldwide.
Database Details
Role in ACMG Classification
ClinVar serves two distinct functions in Helix Insight. First, it provides evidence criteria (PS1, PP5, BP6) based on prior clinical assertions. Second, it provides a classification override mechanism for variants with established clinical significance and no conflicting computational evidence.
Same amino acid change reported as Pathogenic or Likely Pathogenic with >= 2 review stars. The higher star threshold reflects greater confidence in the clinical assertion.
Pathogenic or Likely Pathogenic with >= 1 review star but < 2 stars. Lower confidence tier than PS1. Retained for maximum sensitivity despite ClinGen SVI retirement recommendation.
Benign or Likely Benign with >= 1 review star. Retained for maximum sensitivity despite ClinGen SVI retirement recommendation.
ClinVar classification is applied directly when no conflicting computational evidence exists and review stars >= 1. ClinVar VUS does not override computational classification. Override is subordinate to BA1 and high-confidence conflict checks.
ClinVar Pathogenic Rescue
During quality filtering (Stage 2), variants that fail quality thresholds are normally excluded from classification. However, variants with ClinVar Pathogenic or Likely Pathogenic status are rescued and retain their quality-pass flag regardless of quality metrics. This ensures that known pathogenic variants in low-coverage regions are never silently discarded.
Review Star System
ClinVar assigns review stars based on the level of evidence review and submitter agreement. Helix Insight uses these stars to calibrate the strength of ClinVar-derived evidence:
| Stars | Review Status | Meaning | Criteria |
|---|---|---|---|
| 4 | Practice guideline | Classification from a recognized clinical practice guideline. | PS1 eligible |
| 3 | Reviewed by expert panel | Classified by a ClinGen Expert Panel (VCEP) with full evidence review. | PS1 eligible |
| 2 | Criteria provided, multiple submitters, no conflicts | Two or more submitters agree, using stated criteria, with no conflicting assertions. | PS1 eligible |
| 1 | Criteria provided, single/conflicting submitters | At least one submitter provided criteria, but there may be conflicts or only one submitter. | PP5/BP6 eligible |
| 0 | No assertion criteria provided | Classification submitted without supporting evidence criteria. | Not used |
Columns Loaded (7)
Aggregate clinical significance: Pathogenic, Likely pathogenic, Uncertain significance, Likely benign, Benign, or Conflicting classifications.
Review status text describing the level of review. Maps to review stars.
Review confidence level from 0 to 4 stars. Determines whether PS1 (>=2 stars) or PP5 (>=1 star) is applied.
Unique ClinVar variation identifier. Links to the ClinVar web entry for full submission details.
dbSNP rsID associated with the ClinVar entry, if available.
Condition name(s) associated with the clinical assertion. May contain multiple conditions separated by semicolons.
Protein-level HGVS notation from ClinVar. Used for PS1 matching (same amino acid change as established pathogenic).
Limitations
ClinVar submissions vary in quality. A 1-star submission without criteria may reflect older, less rigorous classification practices.
Conflicting classifications (e.g., one submitter says Pathogenic, another says Benign) are flagged but require manual review to resolve.
ClinVar updates monthly. The deployed version may not include the most recent submissions.
Some ClinVar entries reference GRCh37 coordinates that have been lifted over to GRCh38, which may introduce positional ambiguity for complex variants.
ClinVar VUS does not contribute evidence in either direction and does not override computational classification.
Reference
Landrum MJ, et al. "ClinVar: improvements to accessing data." Nucleic Acids Research. 2020;48(D1):D835-D844. PMID: 31777943.