ClinGen Genomic Curation Expert Panels (U24 Clinical Trial Not Allowed)
Deadline: May 25, 2025
5 pm
Amount: Application budgets are limited to $220,000 per year in direct costs and need to reflect the actual needs of the proposed project.
Purpose
Background
Clinical genetic testing is becoming increasingly routine in clinical practice, and genome-scale sequencing is leading to the identification of many genomic variants with vastly differing clinical relevance. Many of these tests reveal a large number of variants of unknown significance (VUS) due to a variant’s rarity or to differences in the interpretation of its role by clinical laboratories or clinicians, potentially leading to inappropriate medical interventions. Though variants have been identified for certain Mendelian disorders, for the majority of variants in the human genome currently, there is no clear understanding of their impact on human health.
NIH established a clinical genomics infrastructure to develop an openly accessible knowledgebase that promotes data sharing and provides standardized infrastructure and tools for determining the clinical relevance of genetic variants through two initiatives: the Clinical Genomics Resource (ClinGen) and the Clinical Variant Database (ClinVar) of clinical variation. ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) is a publicly and freely available database maintained by the National Center for Biotechnology Information (NCBI) that aggregates information about genomic variation and its relationships to human health. ClinGen (https://www.clinicalgenome.org/) is an NHGRI-funded central resource, additionally supported by NCI and NICHD. ClinGen defines the clinical relevance of genes and variants for use in precision medicine and research by standardizing clinical annotation and interpretation of variants and implementing evidence-based expert consensus assertions. ClinGen's integrated infrastructure supports disease/disorder specific Expert Panels to determine the clinical applicability of genes and/or variants utilizing genomic, clinical, computational, and functional data. ClinGen has developed a clinical validity framework for identifying and assigning the level of evidence to support determination of gene-disease relationships. Furthermore, ClinGen has implemented standard approaches for curation and interpretation of both sequence and copy number variants. Variants evaluated by ClinGen-endorsed Expert Panels are deposited in ClinVar. Based on its rigorous and transparent procedures, ClinGen's expert curated variant pathogenicity interpretations have been recognized by the Food and Drug Administration (FDA) as the first public genetic variant database that can be used to validate genetic variant information in regulatory submissions. The ClinGen framework and tools can be found at: https://www.clinicalgenome.org/tools/.
Sharing of genomic data is critical for the determination of clinical significance of a gene and its variants. To that end, ClinVar is a community submission-driven knowledgebase that can receive submissions of varying complexity ranging from primary submitters for a single variant to authoritative assertions of clinical significance prepared by Expert Panels. ClinVar utilizes a four-star rating system to provide information about the level of review of the submissions. ClinVar assigns three stars for ClinGen approved Expert Panel submissions. As a result of their FDA recognition, ClinGen Expert Panel submissions are additionally marked in ClinVar with an FDA Recognized Database label (as an example, see: https://www.ncbi.nlm.nih.gov/clinvar/variation/239906/). ClinGen has developed the procedures to support the formation of Expert Panels along with a suite of curation interfaces and tools to support their Expert Panel curation activities. These procedures, interfaces, and tools facilitate a systematic process for analyzing evidence in a uniform and streamlined manner by Expert Panels.
Currently, ClinGen-established Expert Panels span a number of disease areas including, but not limited to: cardiovascular diseases, hearing loss, hemostasis/thrombosis, hereditary cancers, inborn errors of metabolism, neurodevelopmental disorders, neuromuscular disorders, ocular disorders, and RASopathies. ClinGen continues to consider additional disease areas as new opportunities arise, as well as new genes or variants within existing domains (https://www.clinicalgenome.org/affiliation/). ClinGen Expert Panels typically function within an overarching Clinical Domain Working Group (CDWG), which represents a high-level organizational structure covering a broad disease area, and may include multiple different Expert Panels covering specific sub-areas within that domain. Externally formed Expert Panels are expected to integrate into an appropriate CDWG. In cases where the proposed disease area does not fall within an established CDWG, ClinGen will oversee the Expert Panel’s activity until an appropriate CDWG is identified or established.
The Expert Panels are required to collaborate with ClinGen and ClinVar utilizing the ClinGen suite of curation interfaces and tools and to submit their underlying data to these resources in order to share data with the field. Training on these tools is required and is provided through ClinGen online resources and/or staff for new curation groups. NIH-funded Expert Panel PD(s)/PI(s), coordinators, and other key staff are expected to participate in ClinGen working groups and share curation procedures and outcomes with ClinGen and ClinVar.
Specific Areas of Research Interest
This NOFO invites applications to establish Genomic Curation Expert Panels. These panels may identify clinical domains of high priority to participating NIH Institutes and Centers (ICs); select candidate genes that will have a high impact on clinical practice in these high priority areas; and analyze all relevant variant data utilizing the ClinGen procedures, interfaces, and tools to make determinations of clinical significance. Specific IC interests include:
Eunice Kennedy Shriver National Institute of Child Health and Human Development: Of particular interest to NICHD are genes associated with gynecologic, andrologic, and reproductive health; poor pregnancy outcomes; high risk newborn conditions; rapid genome sequencing for diagnosing critically ill infants; structural birth defects; intellectual and developmental disabilities; and immunological basis for susceptibility to acute and chronic infections. To the extent possible, NICHD encourages curation efforts that emphasize inclusion of underrepresented populations. NICHD considers applications for pediatric conditions that are the focus of significant efforts at other NIH institutes to be of lower programmatic priority when those institutes are not participating in this NOFO.
National Cancer Institute: Of interest to NCI are genes and germline variants potentially associated with inherited susceptibility to cancer development and/or to cancer response or resistance to therapy; these genes/variants should be curated across populations, with particular attention to underrepresented populations. NCI is also interested in somatic variants of clinical relevance for the diagnosis and treatment of cancer.
National Center for Advancing Translational Sciences: Of interest to NCATS are genes and variants associated with rare diseases.
National Eye Institute: Of interest to NEI are genes and variants associated with diseases of the visual system including those of the eye, central visual, and oculomotor pathways that are within the mission of the NEI. Priorities would be given to candidates that have not been investigated by other ClinGen Expert Panels. The clinical applicability of knowledge gained from the study of specific gene(s) and variant(s) should be addressed in the application.
National Institute of Arthritis and Musculoskeletal and Skin Diseases: Of interest to NIAMS are genes and variants associated with rheumatic, musculoskeletal and skin diseases, within the mission of the NIAMS.
National Institute on Deafness and Other Communication Disorders: Of interest to NIDCD are genes and variants associated with hearing loss (auditory system).
National Institute of Mental Health: Of interest to NIMH are genes and variants associated with severe mental illnesses, such as autism and schizophrenia, within the mission of the NIMH.
National Institute of Neurological Disorders and Stroke: Of interest to NINDS are genes and variants associated with neurological and neuromuscular diseases and stroke within the mission of the NINDS.
Because of the large number of diseases and limited funds for this program, investigators are encouraged to form collaborations with other researchers in the same disease area and submit one application, rather than competing or complementary applications. Disease areas that have already established an Expert Panel should provide compelling justification for the need for support through this initiative.
More Info: https://grants.nih.gov/grants/guide/pa-files/PAR-23-199.html