Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation
Year: 2026
Type: article
Abstract: Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.
Source: Human Genetics
Authors: Sarah Hull, M. Mero, W. Hankey, K. Lee, L. S. Sullivan, R. Ayyagari, M. D. Benson, L. Haer-Wigman, R. B. Hufnagel, H. M. J. Hussain, K. Kämpjärvi, P. A. Sieving, M. Wang, G. Wang, C. Zeitz, R. A. Lewis, R. Chen, K. C. Worley, on behalf of the ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel
Institutions: University of Auckland, Baylor College of Medicine, University of North Carolina at Chapel Hill, The University of Texas Health Science Center at Houston, UC San Diego Health System, University of California San Diego, University of Alberta, Radboud University Medical Center, Kaiser Permanente, Blueprint Genetics (Finland), University of California, Davis, University of California, Irvine, LabCorp (United States), Centre National de la Recherche Scientifique, Institut de la Vision, Inserm, Sorbonne Université
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,690
Awards: Disease modelling to decipher the role and pathogenic mechanism underlying a novel gene defect in rod- cone dystrophy, G3542569142, G4031799020, G4238164613, G4656594441, G4866930200, G4950536974, G5551520971, Enabling Vision Restoration, G6268741103, G6277989666, Sorbonne Universités à Paris pour l'Enseignement et la Recherche, G6842693619, G7080048889, G7240651115, G7376787254, G853170728, G8932038667, G8967381738, G9000103130, G9000159425, G9000169579, Broad-Geisinger Clinical Genome Resource, Unraveling the molecular pathology of retinal degeneration through single cell genomics
OpenAlex ID: W7208794160