Expert curation of clinically significant variants in genes for early onset retinal degeneration

The National Eye Institute awarded the University of California, San Diego a $706,528 cooperative agreement on September 15, 2025, to curate clinically significant genetic variants in genes associated with Leber congenital amaurosis and early-onset retinal dystrophy under the Vision Research program (CFDA 93.867).

The recipient will establish and maintain a Variant Curation Expert Panel within ClinGen, the NIH-sponsored Clinical Genome Resource, to identify clinically actionable variants in LCA and EORD genes and deposit curated variants into the ClinVar database. This work addresses a critical gap in treatment pathways: the absence of uniform, gene-specific classification criteria for variant interpretation that would enable consistent clinical assessment of genetic variants in patients seeking treatment. ClinGen-curated variants deposited in ClinVar constitute an FDA-designated expert-level resource for genetic test interpretation and support personalized patient care. The panel comprises an international group of experts with specialized knowledge in LCA and EORD genetics, clinical care, and variant classification. The curation protocol has been completed for the RPE65 gene and will extend to additional genes for which gene therapies are available or clinical and advanced pre-clinical studies are underway.

Performance occurs in La Jolla, California, with work ending June 30, 2028. The University of Texas Health Science Center at Houston received a $246,237 sub-award on November 18, 2025, to provide expertise in retinal disease gene variant curation, with personnel serving as coordinator, biocurators, and expert panel members.

Abstract

The goal of this proposal is to curate clinically relevant variants in genes associated with the inherited monogenic diseases autosomal recessive leber congenital amaurosis (LCA) and early-onset retinal dystrophy (eord) that cause lifelong blindness beginning in infancy or childhood. More than 30 genes associated with these phenotypes have been identified and the first gene replacement therapy was approved for LCA/eord associated with RPE65 variants. Clinical and pre-clinical trials are currently underway to treat disease caused by other genes. A major limitation in the path to treatment is the lack of uniform classification criteria optimized on a gene-by-gene basis that would enable accurate and consistent interpretation of the clinical relevance of variants found in patients seeking treatment. In a previously funded project we assembled a variant curation expert panel (vcep) within clingen - the NIH-sponsored clinical genome resource - to identify the most clinically important LCA/eord genes and to curate the most clinically actionable variants in those genes. Variants curated within the clingen structure and deposited into clinvar constitute an FDA-designated expert-level resource for interpretation of genetic test results and facilitate delivery of personalized patient care. This LCA/eord vcep is comprised of an international group of experts with in-depth knowledge in LCA/eord genetics and clinical care, with wide-ranging expertise in variant classification. In combination with clingen leadership, the vcep has begun to curate variants in genes associated with LCA/eord phenotypes for which gene therapies are available, or clinical or advanced pre- clinical studies are underway. The clingen protocol for establishing vcep curation activities has been completed for the RPE65 gene and will soon be completed for the GUCY2D gene. The proposed project continues this work and involves two specific aims: 1. Completion of gene-specific rules for AIPL1 and CEP290, which were started under the previous project, and development of specifications for additional LCA/eord genes including LCA5, RDH12, and CRB1, and 2. Sustained curation of variants in each gene as IT is approved by clingen, with attention to building collaborations that will lead to improved curation methods. All steps will be carried out with the approval of the clingen clinical domain working group oversight committee utilizing a suite of variant curation tools and protocols developed by clingen. The proposed project will lead to the development of variant interpretation criteria that are in harmony with rules established for other diseases and optimized for LCA/eord genes, and generate FDA-designated expert level variant classifications in the clinvar public database. This information will advance research on LCA/eord and enable accurate, consistent, high-quality interpretation of genetic test results, and improve patient care. Further, the rules specified by the LCA/eord vcep will advance development of rules for other irds and other hereditary diseases.