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The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation

ClinGen Consortium. Electronic address: splon@bcm.edu et al. Genet Med. 2025 Jan.

Abstract

The Clinical Genome Resource (ClinGen) is a National Institutes of Health-funded program founded 10 years ago that defines the clinical relevance of genes and variants for medical and research use. ClinGen working groups develop standards for data sharing and curating genomic knowledge. Expert panels, with >2500 active members from 67 countries, curate the validity of monogenic disease relationships, pathogenicity of genetic variation, dosage sensitivity of genes, and actionability of gene-disease interventions using ClinGen standards, infrastructure, and curation interfaces. Results are available on clinicalgenome.org and classified variants are also submitted to ClinVar, a publicly available database hosted by the National Institutes of Health. As of January 2024, over 2700 genes have been curated (2420 gene-disease relationships for validity, 1557 genes for dosage sensitivity, and 447 gene-condition pairs for actionability), and 5161 unique variants have been classified for pathogenicity. New efforts are underway in somatic cancer, complex disease and pharmacogenomics, and a systematic approach to addressing justice, equity, diversity, and inclusion. ClinGen's knowledge can be used to build evidence-based genetic testing panels, interpret copy-number variation, resolve discrepancies in variant classification, guide disclosure of genomic findings to patients, and assess new predictive algorithms. To get involved in ClinGen activities go to https://www.clinicalgenome.org/start.

Keywords: Actionability; Clinical genetics; Curation; Data sharing; Dosage.

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Conflict of interest statement

Conflict of Interest Sharon Plon is a member of the Scientific Advisory Board of Baylor Genetics. Leslie Biesecker receives royalties from Wolters-Kluwer, research support from Merck, and is a member of Illumina Medical Ethics Committee. Adam Buchanan has equity in MeTree and You, Inc. Teri Klein is a member of the Scientific Advisory Board of GalateaBio. Courtney Thaxton receives funds from Pharming, Inc. for work on the Antibody Deficiency Variant Curation Expert Panel. All other ClinGen Consortium authors stated that they have no conflict of interest.

Figures

Figure 1:
Figure 1:. The ClinGen expert curation ecosystem has developed into a uniquely synergistic and well-supported global system.
The green outer semicircle represents the infrastructure that underpins the work of the consortium, including standards and frameworks, databases, tools, and curation interfaces to support standardized ClinGen curation, and enables the dissemination of ClinGen expert-curated knowledge to the public via the website and knowledgebases. The blue inner semicircle represents the ClinGen leadership and personnel who ensure high quality curation through consistent integration of and communication with the Expert Panels and the provision of ongoing support and intensive training and guidance. The cornerstone of ClinGen is its international network of global experts and biocurators who contribute to the creation of the curation work products to aid genomic medicine.
Figure 2.
Figure 2.. Results of Expert Curation Across all Four Domains of ClinGen Curation
Depicted here is data summarizing the results for each of the four domains of ClinGen curation described in the paper based on data as of January 2024. We provide the breakdown of the curation results using the framework developed for each curation type. Panel A – Dosage sensitivity including measures of Haploinsufficiency and Triplosensitivity, Panel B – Actionability including both Pediatric and Adult curation results, Panel C- Gene-Disease Validity and Panel D - Variant Pathogenicity.
Figure 3:
Figure 3:. Growth of ClinGen’s Expert Panels and Curation Results Across Funding Phases.
The timeline is based on the three funding phases supported by the National Institutes of Health. Phase 1 (2013 – 2017) focused on the development and implementation of curation frameworks and processes. Phase 2 (2018 – 2021) focused on expansion and dissemination of curation efforts, building of curation interfaces and establishment of global collaborations to maximize the impact of ClinGen curation efforts. Phase 3 (2022 – 2026) is focusing on accelerating the productivity of the variant and gene expert panels (EPs). The graphs depict the timeline for the number of curations (left axis) and the number of expert panels (right axis) for both gene-disease validity and variant pathogenicity curation.
Figure 4.
Figure 4.. The Global ClinGen Network.
As of January 2024, the ClinGen network comprises 2512 active contributors from 67 countries. Countries with members of ClinGen expert panels and/or working groups are colored in blue.
See this image and copyright information in PMC

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