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

> **NIH NIH U24** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $361,134

## Abstract

PROJECT SUMMARY/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)/early-onset Retinal
Degeneration (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, while clinical trials are currently underway to treat disease
caused by 3 other genes (AIPL1, GUCY2D, and CEP290). Despite these advances, it is still challenging to
make accurate clinical diagnoses and decisions based on current knowledge of variants in LCA/eoRD-
associated genes. A major limitation is the lack of uniform classification criteria optimized for gene-disease
specific features that enable accurate and consistent interpretation of the clinical relevance of variants. To
address this, we have assembled a variant curation expert panel (VCEP) comprised of an international group
of experts with in-depth knowledge in LCA/eoRD genetics and clinical care. Further, we established
collaborative relationships with the clinical domain working group (CDWG) oversight committee and the
Ocular CDWG of the NIH-sponsored Clinical Genome Resource (ClinGen) for advice and guidance. With this
leadership team, we propose 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 proposed project
involves 2 Specific Aims: 1. Complete the approval process for the LCA/eoRD VCEP through 4 steps
(assembling a group of experts for LCA/eoRD variant curation, rule specification for the classification of
variants in LCA/eoRD genes using disease-gene specific characteristic features, pilot testing rules specified
for the curation of variants in LCA/eoRD associated genes, and submitting the rules and pilot results to the
ClinGen Sequence Variant Interpretation Working Group for approval), and 2. Curation of variants in selected
LCA/eoRD genes by implementing the specified rules and submission to ClinVar. All steps will be carried out
with the approval of the ClinGen CDWG 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 a comprehensive resource of LCA/eoRD gene variants with 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.

## Key facts

- **NIH application ID:** 10408645
- **Project number:** 1U24EY033699-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JACQUE LYNNE DUNCAN
- **Activity code:** U24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,134
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408645

## Citation

> US National Institutes of Health, RePORTER application 10408645, Expert curation of clinically significant variants in genes for early onset retinal degeneration (1U24EY033699-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10408645. Licensed CC0.

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