bio-clinical-databases-clinvar-lookup

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.
origin	openai4s
category	bioskills/clinical-databases
metadata	{"tool_type":"python","primary_tool":"requests","third_party":{"name":"GPTomics/bioSkills","repository":"https://github.com/GPTomics/bioSkills","commit":"d91ed3d563019e649dc854c56ccd62551359488a","license":"MIT"}}

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 is slow even in best-curated genes.

Submission staleness is non-trivial: ClinVar does not push reclassifications to submitters; a 2017 SCV can persist on an active label in 2026 if the lab has not re-submitted. Genome Alert! (Yauy 2022 Genet Med) was built specifically to detect classification drift between weekly releases. The median delta is ~1,247 classification changes per month with potential clinical impact.

Decision Tree by Query Scenario

Scenario	Recommended path	Why
Single variant, known gene/condition	E-utilities esummary against clinvar DB	Lowest latency, returns VCV-level summary
Batch (10-1000 variants) by HGVS or rsID	myvariant.info with fields=clinvar	Aggregated, includes ClinVar review status
Batch (>1000) or coordinate-based	Local clinvar.vcf.gz with bcftools annotate or cyvcf2	No rate limits; weekly snapshot
Condition-stratified (variant in disease A vs B)	Bulk XML VariationArchive parsing	RCV is the only level that preserves per-condition classification
Cross-database join with gnomAD / dbSNP / COSMIC	ClinGen Allele Registry CA ID	Build-agnostic, transcript-agnostic canonical identifier
Reproducible analysis with citable date	First-Thursday-of-month archive on FTP	Only monthly snapshots are archived; weekly releases disappear

REST API Query (E-utilities)

Goal: Retrieve VCV-level ClinVar summary for a single variant by ID, gene, or HGVS.

Approach: Hit esummary.fcgi or esearch.fcgi against db=clinvar, parse JSON, then optionally hydrate to full record with efetch.

import requests

EUTILS = 'https://eutils.ncbi.nlm.nih.gov/entrez/eutils'

def clinvar_summary(variation_id):
    '''Retrieve VCV-level summary by ClinVar VariationID (do not confuse with CA ID).

    The germline / somatic / oncogenicity classification nesting shown below
    follows the ClinVar 2024 eSummary v2 schema described in the data-access
    documentation. Field names have changed between API versions -- inspect
    the actual JSON returned by eSummary for the live ClinVar version before
    pinning these key paths in production.
    '''
    r = requests.get(f'{EUTILS}/esummary.fcgi',
                     params={'db': 'clinvar', 'id': variation_id, 'retmode': 'json'},
                     timeout=30)
    r.raise_for_status()
    record = r.json()['result'][str(variation_id)]
    return {
        'vcv': record.get('accession'),
        'name': record.get('title'),
        'germline_class': record.get('germline_classification', {}).get('description'),
        'germline_review_status': record.get('germline_classification', {}).get('review_status'),
        'somatic_clinical': record.get('clinical_impact_classification', {}).get('description'),
        'oncogenicity': record.get('oncogenicity_classification', {}).get('description'),
        'last_evaluated': record.get('germline_classification', {}).get('last_evaluated')
    }

def clinvar_search_gene():
    term = 
     pathogenic_only:
        term += 
    r = requests.get(,
                     params={: , : term, : retmax, : },
                     timeout=)
     r.json()[][]

Local VCF Query (Weekly Snapshot)

Goal: Annotate or look up thousands of variants without rate limits.

Approach: Download the weekly clinvar.vcf.gz (note: only first-Thursday-of-month is archived; for longitudinal stability pin to monthly archives), query by genomic coordinates with cyvcf2 or annotate VCFs with bcftools.

mkdir -p clinvar/$(date +%Y%m); cd clinvar/$(date +%Y%m)
wget https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar.vcf.gz
wget https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar.vcf.gz.tbi

from cyvcf2 import VCF

clinvar = VCF('clinvar.vcf.gz')

def lookup(chrom, pos, ref, alt):
    '''Look up by GRCh38 coords. Returns variant-level (VCV) aggregate; not RCV.'''
    for v in clinvar(f'{chrom}:{pos}-{pos}'):
        if v.REF == ref and alt in v.ALT:
            info = v.INFO
            return {
                'vcv_id': info.get('ALLELEID'),
                'clnsig': info.get('CLNSIG'),
                'clnsig_conf': info.get('CLNSIGCONF'),
                'clnrevstat': info.get('CLNREVSTAT'),
                'clndn': info.get('CLNDN'),
                'clnvc': info.get('CLNVC'),
                'clnhgvs': info.get('CLNHGVS'),
                'clndisdb': info.get('CLNDISDB'),
                'oncdn': info.get('ONCDN'),
                'scidn': info.get('SCIDN')
            }
    return None

bcftools annotate \
    -a clinvar.vcf.gz \
    -c INFO/CLNSIG,INFO/CLNREVSTAT,INFO/CLNDN,INFO/CLNVC,INFO/CLNHGVS,INFO/CLNSIGCONF \
    input.vcf.gz -O z -o annotated.vcf.gz
bcftools index -t annotated.vcf.gz

ClinGen Allele Registry (CA IDs): The Real Cross-Database Anchor

ClinGen Allele Registry (https://reg.clinicalgenome.org/) computes a build-agnostic, transcript-agnostic CA ID (format CA######) for any allele projectable onto NCBI references (GRCh37, GRCh38, T2T-CHM13, any RefSeq transcript). The Registry covers ~700M+ alleles, vastly more than ClinVar. CA ID and ClinVar VariationID are one-to-one when a variant exists in ClinVar.

def car_id(hgvs_g):
    '''Resolve HGVS-g to canonical ClinGen Allele Registry CA ID.'''
    r = requests.put(f'https://reg.clinicalgenome.org/allele',
                     headers={'Content-Type': 'text/plain'},
                     data=hgvs_g, timeout=30)
    return r.json().get('@id', '').split('/')[-1] if r.ok else None

Use CA ID for any join touching non-ClinVar resources (gnomAD, dbSNP, COSMIC, MAVEdb). VariationID was renumbered during the 2017 ClinVar schema redesign; treating it as a stable cross-build identifier is unsafe.

Per-Operation Failure Modes

1. Treating CLNSIG as gospel for condition-specific work

• Trigger: Pull CLNSIG=Pathogenic from clinvar.vcf.gz and report variant as pathogenic for the patient's specific phenotype.
• Mechanism: CLNSIG is VCV-level aggregate; a variant can be P for disease A and B for disease B.
• Symptom: Patient phenotype does not match the disease where the variant is actually pathogenic; clinical action is wrong.
• Fix: Parse RCV-level XML (<RCVAccession> per condition); cross-check CLNDN and report per-condition classifications.

2. Parsing legacy XML against 2024 schema

• Trigger: XSLT or parser anchored on <ClinVarSet> or <ClinicalSignificance>.
• Mechanism: 2024 schema replaces both anchors with <VariationArchive> + germline/somatic/oncogenicity tripartite classifications.
• Symptom: Silent zero-record output, no error.
• Fix: Re-target to <VariationArchive> and read GermlineClassification, SomaticClinicalImpact, OncogenicityClassification separately.

3. Counting variant_summary.txt rows naively

• Trigger: wc -l variant_summary.txt to estimate variant count.
• Mechanism: One row per assembly per variant (GRCh37 and GRCh38); double-counts.
• Symptom: Counts inflated ~2x.
• Fix: awk -F'\t' '$17=="GRCh38"' variant_summary.txt | wc -l.

4. Trusting VariationID as a stable cross-build identifier

• Trigger: Join gnomAD-v4 records by ClinVar VariationID.
• Mechanism: VariationIDs were renumbered for a subset of variants during the 2017 schema overhaul.
• Symptom: Spurious mismatches at low rate (~1-2%).
• Fix: Use ClinGen Allele Registry CA ID, which is computed deterministically from sequence.

5. Ignoring star-rating override hierarchy

• Trigger: Pipeline picks the most-recent SCV regardless of review status.
• Mechanism: A 1-star SCV submitted yesterday outranks a 3-star VCEP curation from 2022 by date.
• Symptom: Clinical reports cite outdated or non-expert assertions over expert-panel decisions.
• Fix: Sort by review_status rank (4>3>2>1>0); use the highest-star record. For ties, sort by date.

6. Aggregating "Conflicting" without inspecting the conflict

• Trigger: Treat CLNSIG=Conflicting interpretations as VUS.
• Mechanism: "Conflicting" can mean (P vs LP), (P vs VUS), or (P vs LB); the clinical meaning is completely different across these.
• Symptom: Patients with high-evidence P variants reported as ambiguous; or true VUS reported as actionable.
• Fix: Parse CLNSIGCONF to see exact conflict; weight by submitter star.

7. Missing somatic interpretations

• Trigger: Pre-2024 pipeline reads only CLNSIG.
• Mechanism: Somatic classifications live in new INFO fields (ONCDN, SCIDN, CLNSIGSOMATIC) since 2024.
• Symptom: Cancer variants appear unclassified.
• Fix: Read ONCDN (oncogenicity disease name), SCIDN (somatic clinical impact disease name), and the somatic-specific significance fields.

Reconciliation: When Sources Disagree

Pattern	Likely cause	Action
ClinVar P vs gnomAD AF > 1%	Variant is true founder allele in unstratified gnomAD subset, OR ClinVar P is a stale low-star assertion	Check grpmax_faf95 excluding bottleneck groups; check ClinVar star rating
ClinVar P vs AlphaMissense < 0.1	Variant in NMD-escape region, alternative isoform, or ClinVar P is mis-curated	Check Pejaver 2022 calibration in acmg-classification skill; cross-check VCEP
VCEP 3-star P vs commercial-lab 1-star B	VCEP supersedes for clinical action	Use VCEP; flag submitter for resubmission
ClinVar VCV-level P vs RCV-level VUS for actual condition	VCV averages across conditions	Always report at RCV level for clinical action
ClinVar P vs LOVD/HGMD discordant	LOVD/HGMD use different classification systems; HGMD "DM" != ACMG P	Triangulate against published evidence; do not auto-translate labels
ClinVar P missing for a known disease variant	Submission lag (~6-12 months typical for new findings)	Check published literature; flag for ClinVar submission

Quantitative Thresholds and Operational Conventions

Threshold	Convention	Source
Star >= 2	Acceptable confidence for clinical action without further review	ClinGen SVI operational guidance
Star = 3	VCEP-curated; supersedes lower-star records	ClinGen FDA Recognition 2018
CLNSIG includes 'Pathogenic' OR 'Likely_pathogenic'	Treat as actionable for ACMG	ClinVar field schema
CLNSIGCONF present	Multiple SCVs disagree; do NOT auto-action	ClinVar field schema
Monthly archive	Use first-Thursday-of-month FTP snapshot for reproducible analyses	NCBI FTP retention policy
Submission staleness	Re-check classification annually for active diagnostic variants	Yauy 2022 Genet Med (Genome Alert!)
AF > 5% in gnomAD	BA1 standalone benign per ClinGen SVI default (VCEP overrides exist)	Richards 2015; SVI specs
1247 changes/month	Median variants with classification change per release	Yauy 2022

ClinVar Somatic vs Germline: 2024 Tripartite

The 2024 schema separates three orthogonal classifications, each with its own ReviewStatus and DateLastEvaluated:

• GermlineClassification: Pathogenic / Likely Pathogenic / VUS / LB / B per ACMG/AMP 2015 + SVI.
• SomaticClinicalImpact: Tier I / II / III / IV per AMP/ASCO/CAP 2017 (Li 2017 J Mol Diagn).
• OncogenicityClassification: Oncogenic / Likely Oncogenic / VUS / Likely Benign / Benign per ClinGen/CGC/VICC 2022 oncogenicity framework.

A single VCV can carry all three with distinct evaluations; the legacy "Pathogenic" label is now ambiguous if not qualified by classification type.

Common Errors

Symptom	Cause	Solution
Empty result from efetch db=clinvar	rsID passed where VariationID expected	Use esearch first to resolve rsID to VariationID
CLNSIG is _None or comma-separated mess	Variant has multi-condition RCVs; VCF collapses them	Parse RCV XML for per-condition values
Variant present in ClinVar XML but absent from VCF	Variant lacks GRCh38 coordinates (legacy GRCh37-only submission)	Check <VariationArchive><SequenceLocation> per assembly
2024-format XML parser silently emits zero records	XML schema v2 incompatibility	Re-target to <VariationArchive>
Conflicting interpretations with same star rating across two submitters	True scientific disagreement; sometimes resolved by VCEP later	Apply Tavtigian point system to manually reconcile; flag for VCEP review
Variant has CA ID but no VariationID	Variant in Allele Registry but never submitted to ClinVar	Use AlleleRegistry as canonical; submit to ClinVar if novel pathogenic
CLNSIG says Pathogenic but no associated condition CLNDN	Orphan classification (older submissions)	Treat as low confidence; cross-check publication
Variants pulled by gene return only some isoforms	RefSeq transcript priority differences	Use MANE Select transcript explicitly; cross-check with VEP --mane_select

Anticipated Reviewer Pushback

Pushback	Standard response
"Why is this pathogenic variant 1-star?"	We report star rating per submission; clinical action requires star >=2 OR VCEP curation per ClinGen SVI 2018.
"ClinVar says P but gnomAD AF = 2%"	Reconciled via Whiffin FAF95 max-credible-AF framework; bottleneck-group rule applied.
"This VCV count differs from ClinVar.gov"	We pulled from the monthly archive (first-Thursday-of-month) for reproducibility; the live web is post-most-recent-weekly.
"Why wasn't the somatic variant flagged?"	Pre-2024 XML schema had no separate somatic field; we now read ONCDN/SCIDN/SomaticClinicalImpact per v2 schema.
"VarSome says LP but this says VUS"	Tool-specific aggregation rule differences; VarSome auto-applies PP3+PM2 by default per Tavtigian point system; we apply VCEP-specific PP3 calibration per CSpec.
"rsID match returned wrong variant"	rsID is a cluster identifier; multi-allelic rsIDs require allele-level resolution; we use SPDI or CA ID.
"Why retest a 2022-curated variant?"	Classifications drift as evidence accrues; ClinGen recommends annual re-review for active diagnostic variants.

References

• Landrum MJ et al. 2025. ClinVar: updates to support classifications of both germline and somatic variants. Nucleic Acids Res 53(D1):D1313.
• Harrison SM et al. 2017. Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. Genet Med 19:1096.
• Yauy K et al. 2022. Genome Alert! a standardized procedure for genomic variant reinterpretation and automated gene-phenotype reassessment. Genet Med 24:1316.
• Tavtigian SV et al. 2018. Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet Med 20:1054.
• Tavtigian SV et al. 2020. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat 41:1734.
• Richards S et al. 2015. Standards and guidelines for the interpretation of sequence variants. Genet Med 17:405. (Original ACMG/AMP 2015)
• Pejaver V et al. 2022. Calibration of computational tools for missense variant pathogenicity classification. Am J Hum Genet 109:2163.
• Abou Tayoun AN et al. 2018. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat 39:1517.
• Brnich SE et al. 2020. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework. Genome Med 12:3.
• Li MM et al. 2017. Standards and guidelines for the interpretation and reporting of sequence variants in cancer. J Mol Diagn 19:4. (AMP/ASCO/CAP somatic framework)
• ClinGen Allele Registry: https://reg.clinicalgenome.org/docs/cg-car/
• CSpec Registry: https://cspec.genome.network/cspec/ui/svi/all

Related Skills

• clinical-databases/acmg-classification - ACMG/AMP framework, PVS1 decision tree, Pejaver calibrated PP3/BP4 thresholds, Bayesian point system
• clinical-databases/myvariant-queries - Aggregated queries including ClinVar overlay
• clinical-databases/variant-prioritization - Rare-disease filtering pipeline using ClinVar
• clinical-databases/gnomad-frequencies - Population frequency for BS1/BA1 cross-check
• variant-calling/clinical-interpretation - Clinical reporting workflow