Clinvar Lookup

What the source does

• FilesystemNone observedNo reads or writes in the source
• NetworkNone observedNo outbound calls in the source
• ShellNone observedNo commands run in the source
• DependenciesPinnedNothing floats
• SecretsNone foundNo keys in source

Five audit layers

Gates applied: no behavioural pass.

Audit 0.4.1 · source sha c8c1fc3a2b13 · 19 Oct 2026Report an issue or request a re-scan

• PublisherGPTomics GitHub organizationOwner of the repository this skill is read from
• Source folderGPTomics/bioSkills/clinical-databases/clinvar-lookupThe exact folder we audited
• LicenceMITAs the repository states it
• Commit pinned for this verdictc8c1fc3a2b13A new audit runs when the source changes
• Repository statusArchivedLast push 65 days ago
• Sandboxed runNot runSkills are read, not executed; layer L4 is skipped

Its description: Queries ClinVar for variant pathogenicity classifications, ClinGen VCEP curations, and somatic-vs-germline interpretations via REST API, weekly VCF, or bulk XML. Use when determining clinical significance, triangulating…

---
name: bio-clinical-databases-clinvar-lookup
description: Queries ClinVar for variant pathogenicity classifications, ClinGen VCEP curations, and somatic-vs-germline interpretations via REST API, weekly VCF, or bulk XML. Use when determining clinical significance, triangulating conflicting interpretations, or aggregating evidence against the ACMG/AMP framework with ClinGen SVI specifications.
tool_type: python
primary_tool: requests
---

## Version Compatibility

Reference examples tested with: requests 2.31+, cyvcf2 0.30+, pandas 2.2+, bcftools 1.19+, Entrez Direct 21.0+, lxml 5.0+ (for v2 XML schema).

Before using code patterns, verify installed versions match. If versions differ:
- Python: `pip show <package>` then `help(module.function)` to check signatures
- CLI: `<tool> --version` then `<tool> --help` to confirm flags

If code throws ImportError, AttributeError, or TypeError, introspect the installed package and adapt the example to match the actual API rather than retrying. ClinVar XML schema v2 (rolled out in 2024) replaces `<ClinVarSet>` with `<VariationArchive>` as the top-level anchor; XSLT or parsers targeting the legacy element silently emit zero records.

# ClinVar Lookup and Clinical-Significance Triangulation

**'Look up the clinical significance of this variant'** -> Retrieve ClinVar VCV-level aggregate, SCV-level submissions, ClinGen Variant Curation Expert Panel (VCEP) overrides, and conflict-resolution status.

- Python (REST): `requests.get()` against the E-utilities `clinvar` database
- Python (local VCF): `cyvcf2.VCF('clinvar.vcf.gz')` for batch queries against the weekly snapshot
- CLI: `bcftools annotate -a clinvar.vcf.gz -c INFO/CLNSIG,INFO/CLNREVSTAT,INFO/CLNDN`
- Cross-database: ClinGen Allele Registry CA ID via `https://reg.clinicalgenome.org/`

## The Identifier Hierarchy (VCV / SCV / RCV): Get This Wrong and Everything Downstream Breaks

| Level | Format | What it aggregates | When to use | Fails when |
|-------|--------|--------------------|-------------|-----------|
| **SCV** | `SCVxxxxxxxxx.N` | One submitter, one variant, one condition (atomic submission unit) | Auditing who said what; conflict triangulation | Aggregated reporting (use VCV); cross-condition analysis |
| **RCV** | `RCVxxxxxxxxx.N` | All SCVs for a single (variant, condition) pair | Condition-stratified analysis; legacy aggregation | Variant-level reporting across all conditions (use VCV) |
| **VCV** | `VCVxxxxxxxxx.N` | All RCVs for one variant across all conditions | Canonical anchor since 2017; default API entrypoint | Condition-specific clinical action (use RCV); CLNSIG collapses multi-condition |

**Operational footgun:** the `clinvar.vcf.gz` `CLNSIG` field is the *variant-level* (VCV) aggregate. A variant Pathogenic for disease A but VUS for disease B collapses to "Pathogenic/Conflicting". For condition-stratified analysis, parse RCV-level XML, never `CLNSIG` alone.

**2024 XML schema overhaul:** ClinVar v2 XML separates `GermlineClassification`, `SomaticClinicalImpact`, and `OncogenicityClassification` under one `<VariationArchive>` anchor. The legacy `<ClinicalSignificance>` element is gone. Pipelines built before September 2024 against `<ClinVarSet>` silently emit zero records on new XML. The dual-release period ended December 2024.

## Star Ratings and the Override Hierarchy

| Stars | Review status | What it means operationally |
|-------|--------------|---------------------------|
| 4 | Practice guideline | ACMG/CAP CFTR-level (vanishingly rare) |
| 3 | Expert panel reviewed (ClinGen VCEP) | **FDA-recognized tier**; overrides lower-star records for clinical action |
| 2 | Multiple submitters, criteria provided, no conflicts | Reliable aggregate |
| 1 | Single submitter OR conflicting interpretations (often mis-reported as 2-star) | Use with scrutiny |
| 0 | No assertion criteria provided | Literature-only or legacy submissions |

ClinVar does NOT retract or hide lower-star records when a VCEP publishes; a variant can simultaneously display "Pathogenic (3-star VCEP)" and "Conflicting interpretations (1-star)". Tools handle this differently (VarSeq, Franklin, GenoOx each pick a winner via different rules); this is a major source of inter-tool disagreement.

## ClinGen Variant Curation Expert Panels (VCEPs)

As of 2025, ~80-90 VCEPs are approved or in progress across RASopathies, hereditary cancer (ENIGMA BRCA1/2, InSiGHT MMR), cardiomyopathy (sarcomere genes), hearing loss, RPE65/IRD, inborn errors of metabolism, and FH. The current count is moving; the authoritative directory is the Criteria Specification Registry at `https://cspec.genome.network/cspec/ui/svi/all`.

Each VCEP publishes a **gene-disease-specific CSpec** that re-weights ACMG/AMP criteria. The Hearing Loss VCEP downgrades PM2 to supporting by default and upgrades PS3 thresholds for OTOF. Treating "ACMG/AMP" as a single rubric across all genes is the most common error in non-specialist tooling.

## ACMG/AMP, ClinGen SVI Specifications, and the Bayesian Point System

The Richards 2015 28-criterion framework is the foundation, but **every modern automated classifier (InterVar, GeneBe, Franklin, VarSome) implements the Tavtigian 2018/2020 Bayesian point system**, not the original combining rules. Strengths map to points: Supporting=1, Moderate=2, Strong=4, Very Strong=8 (benign codes negative). Final categories: P >=10, LP 6-9, VUS 0-5, LB -1 to -6, B <=-7.

For variant interpretation framework details, calibrated in-silico thresholds, and PVS1 decision-tree logic, defer to `clinical-databases/acmg-classification`. This skill focuses on querying ClinVar; it intentionally does not re-implement classification.

## Conflicting Interpretations and Conflict Resolution

Harrison 2017 *Genet Med* 19:1096 (PMID 28301460) showed 87% of inter-lab conflicts were resolvable by reassessment plus data sharing. As of 2024, only 3.8% of conflicting BRCA1 missense VUS reached consensus despite years of effort; conflict resolution i

Excerpt, first 6,000 characters of SKILL.md, verbatim from the audited commit. It is text from someone else’s repository, quoted so you can judge it before your agent reads it.

pip install requests cyvcf2 pandas lxml

git clone https://github.com/GPTomics/bioSkills
git -C bioSkills checkout c8c1fc3a2b13

Works in

1. 2026-10-19
   ✓SAFE B 89 / 100

   first audit · source c8c1fc3a2b13

Questions about Clinvar Lookup

• github.com/GPTomics/bioSkills/tree/main/clinical-databases/clinv — the audited source at commit c8c1fc3a2b13 and every finding aboveObserved · 19 Oct 2026

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