ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel (XLIRD VCEP): RPGR Curation Progress, and Initial modified ACMG criteria for RS1 and CHM

Abstract

Purpose : As part of the Clinical Genome Resource (ClinGen), the X-linked Inherited Retinal Diseases Variant Curation Expert Panel (XLIRD VCEP) was established in 2020 to address the need for consistent variant interpretation in inherited retinal disease (IRD) genes with an X-linked inheritance pattern, which account for ~15% of IRD reported in large cohorts.

Methods : The XLIRD VCEP adapts and implements the ClinGen variant curation practices that have been recognized by the U.S. FDA to assess individual variants in seven X-linked genes (CACNA1F, CHM, NPD, OFD1, RPGR, RP2, and RS1). By combining expertise in phenotypes and molecular mechanisms of the IRD from clinical and laboratory experts, a set of variant curation rules customized to each gene is specified to assess the pathogenicity of the variants. All reported variants in the seven genes are systematically scored, following the rules and categorized into five classes, including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign, according to ACMG/AMP guidelines.

Results : The XLIRD VCEP, with membership and curation protocols available (https://clinicalgenome.org/), has developed and refined with pilot curation exercises, gene-specific rules for RPGR (cause of 9% of rod-cone and cone-rod dystrophies). The approved rules will be applied to curate RPGR variants. Initial rules for RS1 have been generated, and pilot curation exercises planned. CHM rules are being defined. We employ computational prediction methods for functional impact and splicing consequences, and selected population allele frequencies to determine variant pathogenicity. To facilitate the curation process, private variant data from genetic testing are also collected. This process will be repeated for the other XLIRD genes, and curations reviewed iteratively to refine the processes further. Variants curated by the approved rules will carry a 3-star label in the ClinVar database.

Conclusions : Systematic, consistent variant curation with gene-specific guidelines will evaluate current variant classifications, increase documented evidence and decrease the numbers of VUS within these XLIRD genes. Improving specificity and accuracy of molecular diagnoses of patients and increasing the value of genetic testing as a diagnostic tool and guide for eligibility for IRD genetic therapies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.