Skip to content

CURATION_CRITERIA_GUIDE.md

Latest commit

 

History

History
335 lines (250 loc) · 13.5 KB

CURATION_CRITERIA_GUIDE.md

File metadata and controls

335 lines (250 loc) · 13.5 KB

ClinVar SCV Curation Criteria Guide

This document outlines the conditions and criteria for when curators should tag submissions (SCVs) with specific actions and reasons in the ClinVar Curation Chrome Extension.

Overview of Actions

The extension supports three curation actions:

Action Purpose Reason Required?
Flagging Candidate Mark SCV submissions that may need re-assessment or removal to improve ClinVar data quality Yes
Remove Flagged Submission Process SCV submissions that were previously flagged for removal Yes
No Change Document that an SCV has been reviewed and no action is needed No

Action 1: Flagging Candidate

Use this action when an SCV submission has quality issues that warrant potential removal or re-assessment. Reasons are organized into three categories.

Category 1: Submission Errors

These reasons address fundamental submission mistakes.

"New submission from submitter that appears to have been intended to update this older submission"

When to use:

  • The same submitter has created a newer SCV for the same variant
  • The older submission appears to be superseded by the new one
  • The submitter likely intended to update their existing submission but created a duplicate instead
  • Both submissions exist in ClinVar, creating unnecessary conflict or redundancy

Evidence to look for:

  • Multiple SCVs from the same submitter for the same variant
  • Newer submission has more recent evaluation/submission date
  • Newer submission may have updated interpretation or additional evidence
  • Original submission was never updated or removed by the submitter

"Other submission error"

When to use:

  • The submission contains an error that doesn't fit other specific categories
  • There is an obvious data entry mistake in the submission
  • The submission has incorrect variant information, condition mapping, or other data issues
  • Catch-all for submission problems not covered by other reasons

Evidence to look for:

  • Mismatched condition/gene associations
  • Obvious data entry errors
  • Submissions that don't make scientific sense for the variant

Category 2: Unnecessary Conflicting or Case-level Interpretation Submissions

These reasons address submissions that create artificial conflicts or represent inappropriate interpretation types.

"Clinical significance appears to be a case-level interpretation inconsistent with variant classification"

When to use:

  • The submission represents a clinical observation from a single patient case
  • The interpretation is based on a specific patient's phenotype rather than variant-level evidence
  • The clinical significance assigned is inconsistent with proper variant classification standards
  • The submission conflates patient-level findings with variant-level classification

Evidence to look for:

  • Language suggesting case-specific interpretation (e.g., "observed in patient with...")
  • Lack of population-level or functional evidence
  • Classification that doesn't align with ACMG/AMP guidelines for the available evidence
  • Evidence is primarily or solely clinical observation from case(s)

"Unnecessary conflicting claim for distinct condition when other classifications are more relevant"

When to use:

  • The submission asserts a classification for a condition that creates unnecessary conflict
  • Other submissions with more relevant condition associations exist
  • The conflicting claim is for a distinct/different condition than more authoritative submissions
  • The conflict doesn't provide meaningful additional information

Evidence to look for:

  • Multiple conditions associated with the variant
  • The flagged submission's condition association is less relevant than others
  • Other submissions (especially from VCEPs or larger labs) provide more appropriate classifications
  • The conflict detracts from clarity rather than adding scientific value

Category 3: Old/Outlier/Unsupported Submissions

These reasons address submissions that lack current scientific support or contradict expert-reviewed evidence.

"Older and outlier claim with insufficient supporting evidence"

When to use:

  • The submission is both old (outdated) AND an outlier compared to other submissions
  • The classification differs significantly from the consensus of other submitters
  • The supporting evidence is insufficient by current standards
  • Combines the criteria of being both temporally outdated and scientifically isolated

Evidence to look for:

  • Old evaluation/submission date (relative to other submissions)
  • Classification that disagrees with majority of other submitters
  • Minimal or no evidence provided to support the outlier position
  • Evidence cited is outdated or has been superseded

"Older claim that does not account for recent evidence"

When to use:

  • The submission predates significant new evidence about the variant
  • New publications, functional studies, or population data have emerged since the submission
  • The classification might change if the submitter incorporated newer evidence
  • The submission hasn't been updated despite availability of relevant new data

Evidence to look for:

  • Old evaluation date compared to available evidence
  • Publications or ClinGen classifications that post-date the submission
  • Population frequency data (gnomAD updates) not reflected in submission
  • Functional evidence that emerged after the submission date

"Claim with insufficient supporting evidence"

When to use:

  • The submission lacks adequate evidence regardless of age
  • The classification cannot be justified based on provided supporting data
  • Does not meet evidence thresholds for the asserted classification
  • Evidence quality or quantity is inadequate for the interpretation

Evidence to look for:

  • Missing or vague assertion method
  • No citations or minimal citations provided
  • Evidence doesn't meet ACMG/AMP criteria for the classification level
  • Review status of "no assertion criteria provided" or similar

"Outlier claim with insufficient supporting evidence"

When to use:

  • The submission disagrees with the consensus of other submitters
  • The outlier position is not supported by sufficient evidence
  • There's no compelling scientific rationale for the differing classification
  • The submission creates conflict without adequate justification

Evidence to look for:

  • Classification differs from majority/consensus
  • Other submitters (especially expert panels) have different classifications
  • Limited or unconvincing evidence to justify the outlier position
  • No recent updates to address the conflicting interpretations

"Conflicts with expert reviewed submission without evidence to support different classification"

When to use:

  • A VCEP (Variant Curation Expert Panel) or Expert Panel has reviewed the variant
  • The flagged submission conflicts with the expert-reviewed classification
  • The submitter has not provided evidence sufficient to justify disagreeing with expert review
  • Expert panel review represents a higher standard of evidence review

Evidence to look for:

  • Presence of an expert panel submission (review status: "reviewed by expert panel")
  • Conflicting classification from the flagged submission
  • Flagged submission lacks equivalent quality evidence
  • No compelling new evidence that would warrant different classification

"P/LP classification for a variant in a gene with insufficient evidence for a gene-disease relationship"

When to use:

  • The variant is in a gene where the gene-disease relationship is not well established
  • The submission classifies the variant as Pathogenic or Likely Pathogenic
  • ClinGen Gene Curation has not confirmed (or has disputed) the gene-disease relationship
  • The P/LP claim may be premature given uncertain gene validity

Evidence to look for:

  • ClinGen gene-disease validity assessment is "Limited," "Disputed," or "Refuted"
  • No ClinGen gene curation available for the condition
  • The condition assertion may be based on insufficient gene-disease evidence
  • Other scientific literature questions the gene-disease relationship

Category 4: Miscellaneous

These reasons address situations that do not fit neatly into the categories above.

"This phenotype is not a monogenic disease. The terms P/LP are not appropriate."

When to use:

  • The condition associated with the submission is not a monogenic (Mendelian) disease
  • The submitter has classified the variant as Pathogenic or Likely Pathogenic for a complex/multifactorial phenotype
  • The terms P/LP are only appropriate for monogenic disease contexts per ACMG/AMP guidelines
  • The phenotype is better characterized as a risk factor, susceptibility, or complex trait

Evidence to look for:

  • The associated condition is known to be multifactorial or complex (e.g., type 2 diabetes, coronary artery disease, obesity)
  • OMIM or other authoritative sources do not list the condition as monogenic
  • The gene is associated with susceptibility rather than a Mendelian inheritance pattern
  • ACMG/AMP classification framework does not apply to the condition

"Other"

When to use:

  • The submission warrants flagging but does not fit any of the specific reason categories above
  • Use the Notes field to document the specific rationale when selecting this reason

Action 2: Remove Flagged Submission

Use this action when processing submissions that were previously flagged and now need final removal action.

"Other SCVs submitted for VCV record"

When to use:

  • The flagged submission can be removed because other valid SCVs exist
  • Removal won't leave the VCV record without submissions
  • Other submissions adequately represent the clinical significance of the variant

"Gene-disease relationship classification has changed"

When to use:

  • ClinGen or other authoritative sources have updated the gene-disease relationship
  • Previous P/LP classifications are no longer appropriate
  • Gene validity reclassification affects the relevance of the submission

"Discussion with submitter"

When to use:

  • Contact was made with the original submitter
  • Submitter agreed the submission should be removed or updated
  • Follow-up action from prior flagging has been completed

"Curation error"

When to use:

  • The original flagging was made in error
  • Re-review determined the submission shouldn't have been flagged
  • Correcting a prior curation mistake

Action 3: No Change

Use this action when an SCV has been reviewed but no curation action is warranted.

When to use:

  • The submission has been evaluated and found to be appropriate
  • The submission may be old or differ from consensus but has valid supporting evidence
  • The submitter's classification is defensible given their evidence and methods
  • Review confirms the submission contributes meaningfully to ClinVar
  • You want to document that an SCV was reviewed (audit trail)

Reason is optional for "No Change" actions. Use the Notes field to document your rationale if desired.

Decision Tree Summary

Review SCV Submission
         │
         ├── Is there an obvious submission error?
         │         │
         │         ├── YES → Flagging Candidate: [Submission errors category]
         │         │
         │         └── NO ↓
         │
         ├── Is it a case-level interpretation or unnecessary conflict?
         │         │
         │         ├── YES → Flagging Candidate: [Unnecessary Conflicting category]
         │         │
         │         └── NO ↓
         │
         ├── Is it old, an outlier, or lacking evidence?
         │         │
         │         ├── YES → Flagging Candidate: [Old/Outlier/Unsupported category]
         │         │
         │         └── NO ↓
         │
         ├── Is the phenotype non-monogenic or does another miscellaneous reason apply?
         │         │
         │         ├── YES → Flagging Candidate: [Miscellaneous category]
         │         │
         │         └── NO ↓
         │
         ├── Was this SCV previously flagged and needs removal action?
         │         │
         │         ├── YES → Remove Flagged Submission: [Select appropriate reason]
         │         │
         │         └── NO ↓
         │
         └── Submission is acceptable
                   │
                   └── No Change (optionally document in notes)

Key Data Points to Consider During Review

When evaluating an SCV, curators should examine:

  1. SCV Metadata

    • Submitter name and ID
    • Submission date and evaluation date
    • Review status (criteria provided, expert panel, etc.)
    • Assertion method

  2. Classification Details

    • Clinical interpretation (P, LP, VUS, LB, B)
    • Associated condition(s)
    • Allele origin

  3. Context from VCV

    • Overall VCV classification and review status
    • Other SCVs on the same VCV
    • Expert panel submissions present?
    • Total number and consensus of submissions

  4. External Resources

    • ClinGen gene-disease validity
    • Recent publications
    • gnomAD population frequency data
    • ACMG/AMP guideline alignment

Version History

Version Date Changes
1.0 December 2025 Initial documentation based on extension v3.2
1.1 June 2026 Added Category 4: Miscellaneous with new phenotype reason; updated for extension v3.4

This document is based on the ClinVar Curation Chrome Extension v3.4 codebase and associated release notes.