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ClinGen — Clinical Genome Resource

Overview

The Clinical Genome Resource (ClinGen) is an expert-panel consortium that develops the standards and authoritative classifications defining the clinical relevance of genes and variants for medical and research use. Funded by the NIH NHGRI since 2013 and now spanning more than 2,500 active expert panel members from 67 countries, it operates as a community standards-development body. Its working groups and Variant Curation Expert Panels build evidence-based curation frameworks and apply them to assess gene-disease validity, variant pathogenicity, dosage sensitivity, and clinical actionability. Its classifications are submitted to ClinVar and are treated as the highest-tier evidence in variant interpretation, taking precedence over individual laboratory submissions. The FDA formally recognised ClinGen’s germline variant curations as a valid source of accurate human variant interpretation data in December 2018.

Curation activities

ClinGen’s expert panels run three principal curation workflows, each producing a defined classification backed by a published evidence framework:

  • Gene-disease validity asks whether there is sufficient evidence that variation in a gene causes a specific disease. Each gene-disease pair is scored with a semi-quantitative framework and assigned one of six classifications: Definitive, Strong, Moderate, Limited, Disputed, or Refuted. The ACMG recommends that diagnostic gene panels include only Definitive, Strong, or Moderate relationships. As of January 2024, over 2,420 relationships had been curated.
  • Variant pathogenicity applies ClinGen-specified refinements to the ACMG/AMP 2015 variant classification guidelines. Variant Curation Expert Panels (VCEPs) develop gene-specific criteria and submit curated variants directly to ClinVar. As of January 2024, 5,161 unique variants had been classified.
  • Dosage sensitivity assesses whether haploinsufficiency or triplosensitivity of a gene or genomic region causes disease. As of January 2024, 1,557 genes had been evaluated.

Neuroscience relevance

ClinGen operates expert panels covering hereditary neurological diseases, including hereditary spastic paraplegia, hereditary ataxia, Rett syndrome, brain malformations, and epilepsy genetics. These panels produce the authoritative gene-disease classifications used by neurogenetics laboratories worldwide. ENIGMA (which has a node) collaborates with ClinGen on cancer predisposition classification, and there is growing alignment between the ENIGMA/ClinGen community and clinical neurological disease curation.

Connections

  • registeredIn: ClinVar
  • implements: HPO (phenotype vocabulary)
  • implements: MONDO (disease ontology)
  • implements: VRS (ClinGen Allele Registry assigns VRS-compatible identifiers)

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