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ClinGen — Clinical Genome Resource

Overview

The Clinical Genome Resource (ClinGen) is an NIH NHGRI-funded programme that defines the clinical relevance of genes and variants for medical and research use. Founded in 2013 and now spanning more than 2,500 active expert panel members from 67 countries, ClinGen develops evidence-based frameworks and operates expert panels that systematically curate the gene-disease validity, variant pathogenicity, dosage sensitivity, and actionability of genomic findings. Its classifications are submitted to ClinVar and are considered 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

Gene-disease validity curation answers the question: is there sufficient evidence that variation in this gene causes a specific disease? ClinGen evaluates each gene-disease pair using a semi-quantitative scoring framework and assigns one of six classifications: Definitive, Strong, Moderate, Limited, Disputed, or Refuted. As of January 2024, over 2,420 gene-disease relationships have been curated for validity. The ACMG recommends that diagnostic gene panels include only relationships classified as Definitive, Strong, or Moderate. Variant pathogenicity curation 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 have been classified. Dosage sensitivity curation assesses whether haploinsufficiency or triplosensitivity of a gene or genomic region causes disease. As of January 2024, 1,557 genes have 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

  • Funded by: NIH / NHGRI
  • Submits to: ClinVar
  • Uses: HPO (phenotype vocabulary), MONDO (disease ontology)
  • Variant format: VRS (ClinGen Allele Registry assigns VRS-compatible identifiers)

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