June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
ClinGen Variant Curation for X-linked Inherited Retinal Disease Genes
Author Affiliations & Notes
  • Kim C. Worley
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Kristy Lee
    Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States
  • Radha Ayyagari
    Veterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, California, United States
  • Michael E Cheetham
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Elfride De Baere
    Center for Molecular Genetics, Universitair Ziekenhuis Gent Maag- darm- en leverziekten en voedingsproblemen kinderen, Gent, Oost-Vlaanderen, Belgium
    Department of Biomolecular Medicine, Universiteit Gent, Gent, Belgium
    National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
  • Robert K Koenekoop
    Division of Paediatric Ophthalmology, McGill University Faculty of Medicine and Health Sciences, Montreal, Quebec, Canada
  • Linyan Meng
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Department of Ophthalmology, UCSF Medical Center, UCSF Medical Center, San Francisco, CA, US, health/system, California, United States
  • Paul A Sieving
    Ophthalmology and Vision Science, University of California Davis, Davis, California, United States
  • Lori S Sullivan
    Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States
  • Christina Zeitz
    Institut de la vision, Paris, Île-de-France, France
  • Rui Chen
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Kim Worley Baylor Genetics, Code F (Financial Support); Kristy Lee None; Radha Ayyagari None; Michael Cheetham ProQR, Alia Therapeutics, PYC, Code C (Consultant/Contractor); Elfride De Baere Janssen Global Services, LLC, XLRP Virtual Regional Advisory Board (Europe), Code C (Consultant/Contractor); KERRY GOETZ None; Robert Koenekoop ProQR, Biogen, Novartis, Editas, Aequus and MeiraGTX, Code C (Consultant/Contractor), Fighting Blindness Canada, Vision Health Research Network (Quebec) NIH 1R01 EY 030499-01, Code F (Financial Support); Linyan Meng Baylor Genetics, Code E (Employment); MAXENCE NACHURY None; Paul Sieving None; Lori Sullivan None; Christina Zeitz None; Rui Chen None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 624 – A0339. doi:
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      Kim C. Worley, Kristy Lee, Radha Ayyagari, Michael E Cheetham, Elfride De Baere, KERRY GOETZ, Robert K Koenekoop, Linyan Meng, MAXENCE NACHURY, Paul A Sieving, Lori S Sullivan, Christina Zeitz, Rui Chen; ClinGen Variant Curation for X-linked Inherited Retinal Disease Genes. Invest. Ophthalmol. Vis. Sci. 2022;63(7):624 – A0339.

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      © ARVO (1962-2015); The Authors (2016-present)

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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 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 : We established the XLIRD VCEP, with membership and curation protocols available on the ClinGen website (https://clinicalgenome.org/). Starting with RPGR, in which variants account for 9% of rod-cone and cone-rod dystrophies, gene-specific curation rules are generated. Performance of various computational prediction tools are evaluated, and proper allele frequencies in population databases are selected to determine the pathogenicity of the variant. To facilitate the curation process, in addition to published variants, private variant data from genetic testing laboratories are also collected. Pilot curation exercises being performed will be evaluated to refine the initial rules, which will then be applied to curate variants in the RPGR gene. This process will be repeated for the other XLIRD genes, and the curations reviewed iteratively to refine the processes further.

Conclusions : Systematic and consistent curation of variants from FDA-recognized gene-specific guidelines supported by sharing genomic data and expertise will evaluate the current classification of variants and decrease the numbers of VUS within these XLIRD genes. This will improve the specificity and accuracy of the molecular diagnoses of patients with variants in these genes and increase the value of genetic testing as a diagnostic tool and guide for patient eligibility for genetic therapies for these IRD.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.


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