ClinVar

ClinVar is a free, public archive operated by NCBI (part of the National Institutes of Health) that catalogs claimed relationships between human genetic variants and phenotypes — inherited disease, cancer, and drug response — along with the supporting evidence and the classification each submitter assigns. A first complete public release went live in April 2013, following a 2012 preliminary version, and it has become the central clearinghouse clinical laboratories and researchers check before reporting a variant’s clinical significance.

What ClinVar actually stores

ClinVar is not a single flat table of “variant = meaning.” It aggregates submissions at three levels: an SCV record is one submitter’s individual assertion about a variant-condition pair; an RCV record aggregates every submission made about the same variant-condition pair, so a reader can see whether submitters agree or conflict; and a VCV record rolls up every condition ever reported for a given variant across all conditions. Variants are described using standard HGVS nomenclature, and conditions are mapped to MedGen, NCBI’s controlled vocabulary that consolidates medical terminology drawn from multiple source vocabularies into one concept per condition.

Classification categories

For germline variants, ClinVar accepts the five-tier terminology recommended by the ACMG/AMP 2015 variant-interpretation guidelines: Pathogenic, Likely pathogenic, Uncertain significance (the well-known “VUS”), Likely benign, and Benign — plus ClinGen-recommended terms for low-penetrance and risk-allele variants (e.g. “Pathogenic, low penetrance,” “Uncertain risk allele”), and non-Mendelian categories such as drug response, association, and protective. Because different submitters can classify the same variant differently — using different evidence, different guideline versions, or different in-house criteria — a single ClinVar RCV record commonly shows conflicting classifications; ClinVar displays this disagreement rather than resolving it, leaving clinical interpretation to the reader.

Who submits, and the ClinGen relationship

Submitters include clinical diagnostic laboratories, research groups, expert panels, and literature-curation groups; submissions range from a bare classification to detailed case-level and functional evidence. ClinVar is an active data partner of ClinGen (the Clinical Genome Resource), the NIH-funded initiative that convenes disease- and gene-specific expert panels to adjudicate variant classifications using standardized, more rigorous evidence review; ClinGen expert-panel classifications are submitted into and displayed within ClinVar, carrying additional weight (a three- or four-star review status) over an unreviewed single-lab submission.

Examples

• A clinical diagnostic lab identifies a BRCA1 variant in a patient sample and submits its classification (with supporting family-history and functional evidence) to ClinVar as an SCV record, contributing to the variant’s aggregate RCV record alongside any other labs that have reported the same variant.
• A researcher building a genomic-medicine pipeline queries ClinVar’s API to automatically flag any patient variant with a “Pathogenic” or “Likely pathogenic” classification and a three-star ClinGen expert-panel review status, prioritizing it for manual review over an unreviewed single-submitter classification.

Counter-example

A novel variant identified in a research sequencing study that has not been submitted to ClinVar is not “in ClinVar” simply because it is medically relevant — ClinVar only contains what submitters have actively deposited; absence from ClinVar means no submitter has yet reported the variant, not that the variant has been reviewed and found insignificant.

Related infrastructure

ClinVar sits alongside dbGaP in NCI/NIH’s genomic-data ecosystem but serves a different purpose: dbGaP archives underlying study-level genotype-phenotype data under controlled access, while ClinVar archives open, variant-level clinical-significance claims intended for exactly the kind of broad reuse a diagnostic lab or clinician needs at the point of care.