011 Clinvar 6bf32841

ClinVar API and Data Access Reference

Overview

ClinVar provides multiple methods for programmatic data access:

• E-utilities - NCBI's REST API for searching and retrieving data
• Entrez Direct - Command-line tools for UNIX environments
• FTP Downloads - Bulk data files in XML, VCF, and tab-delimited formats
• Submission API - REST API for submitting variant interpretations

E-utilities API

Base URL

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/

Supported Operations

1. esearch - Search for Records

Search ClinVar using the same query syntax as the web interface.

Endpoint:

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Parameters:

• db=clinvar - Database name (required)
• term=<query> - Search query (required)
• retmax=<N> - Maximum records to return (default: 20)
• retmode=json - Return format (json or xml)
• usehistory=y - Store results on server for large datasets

Example Query:

# Search for BRCA1 pathogenic variants
curl "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?db=clinvar&term=BRCA1[gene]+AND+pathogenic[CLNSIG]&retmode=json&retmax=100"

Common Search Fields:

• [gene] - Gene symbol
• [CLNSIG] - Clinical significance (pathogenic, benign, etc.)
• [disorder] - Disease/condition name
• [variant name] - HGVS expression or variant identifier
• [chr] - Chromosome number
• [Assembly] - GRCh37 or GRCh38

2. esummary - Retrieve Record Summaries

Get summary information for specific ClinVar records.

Endpoint:

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Parameters:

• db=clinvar - Database name (required)
• id=<UIDs> - Comma-separated list of ClinVar UIDs
• retmode=json - Return format (json or xml)
• version=2.0 - API version (recommended for JSON)

Example:

# Get summary for specific variant
curl "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi?db=clinvar&id=12345&retmode=json&version=2.0"

esummary Output Includes:

• Accession (RCV/VCV)
• Clinical significance
• Review status
• Gene symbols
• Variant type
• Genomic locations (GRCh37 and GRCh38)
• Associated conditions
• Allele origin (germline/somatic)

3. efetch - Retrieve Full Records

Download complete XML records for detailed analysis.

Endpoint:

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi

Parameters:

• db=clinvar - Database name (required)
• id=<UIDs> - Comma-separated ClinVar UIDs
• rettype=vcv or rettype=rcv - Record type

Example:

# Fetch full VCV record
curl "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=clinvar&id=12345&rettype=vcv"

4. elink - Find Related Records

Link ClinVar records to other NCBI databases.

Endpoint:

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi

Available Links:

• clinvar_pubmed - Link to PubMed citations
• clinvar_gene - Link to Gene database
• clinvar_medgen - Link to MedGen (conditions)
• clinvar_snp - Link to dbSNP

Example:

# Find PubMed articles for a variant
curl "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=clinvar&db=pubmed&id=12345"

Workflow Example: Complete Search and Retrieval

# Step 1: Search for variants
SEARCH_URL="https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?db=clinvar&term=CFTR[gene]+AND+pathogenic[CLNSIG]&retmode=json&retmax=10"

# Step 2: Parse IDs from search results
# (Extract id list from JSON response)

# Step 3: Retrieve summaries
SUMMARY_URL="https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi?db=clinvar&id=<ids>&retmode=json&version=2.0"

# Step 4: Fetch full records if needed
FETCH_URL="https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=clinvar&id=<ids>&rettype=vcv"

Entrez Direct (Command-Line)

Install Entrez Direct for command-line access:

sh -c "$(curl -fsSL ftp://ftp.ncbi.nlm.nih.gov/entrez/entrezdirect/install-edirect.sh)"

Common Commands

Search:

esearch -db clinvar -query "BRCA1[gene] AND pathogenic[CLNSIG]"

Pipeline Search to Summary:

esearch -db clinvar -query "TP53[gene]" | \
  efetch -format docsum | \
  xtract -pattern DocumentSummary -element AccessionVersion Title

Count Results:

esearch -db clinvar -query "breast cancer[disorder]" | \
  efilter -status reviewed | \
  efetch -format docsum

Rate Limits and Best Practices

Rate Limits

• Without API Key: 3 requests/second
• With API Key: 10 requests/second
• Large datasets: Use usehistory=y to avoid repeated queries

API Key Setup

1. Register for NCBI account at https://www.ncbi.nlm.nih.gov/account/
2. Generate API key in account settings
3. Add &api_key=<YOUR_KEY> to all requests

Best Practices

• Test queries on web interface before automation
• Use usehistory for large result sets (>500 records)
• Implement exponential backoff for rate limit errors
• Cache results when appropriate
• Use batch requests instead of individual queries
• Respect NCBI servers - don't submit large jobs during peak US hours

Python Example with Biopython

from Bio import Entrez

# Set email (required by NCBI)
Entrez.email = "your.email@example.com"

# Search ClinVar
def search_clinvar(query, retmax=100):
    handle = Entrez.esearch(db="clinvar", term=query, retmax=retmax)
    record = Entrez.read(handle)
    handle.close()
    return record["IdList"]

# Get summaries
def get_summaries(id_list):
    ids = ",".join(id_list)
    handle = Entrez.esummary(db="clinvar", id=ids, retmode="json")
    record = Entrez.read(handle)
    handle.close()
    return record

# Example usage
variant_ids = search_clinvar("BRCA2[gene] AND pathogenic[CLNSIG]")
summaries = get_summaries(variant_ids)

Error Handling

Common HTTP Status Codes

• 200 - Success
• 400 - Bad request (check query syntax)
• 429 - Too many requests (rate limited)
• 500 - Server error (retry with exponential backoff)

Error Response Example

<ERROR>Empty id list - nothing to do</ERROR>

Additional Resources

• NCBI E-utilities documentation: https://www.ncbi.nlm.nih.gov/books/NBK25501/
• ClinVar web services: https://www.ncbi.nlm.nih.gov/clinvar/docs/maintenance_use/
• Entrez Direct cookbook: https://www.ncbi.nlm.nih.gov/books/NBK179288/