Abstract: FR-PO662
The ClinGen Alport Syndrome Variant Curation Expert Panel: Guiding Variant Classification in COL4A3, COL4A4, and COL4A5
Session Information
- Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Byrne, Alicia B., Broad Institute, Cambridge, Massachusetts, United States
- Wongboonsin, Janewit, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand
- Roberts, Mary-Beth, Cleveland Clinic, Cleveland, Ohio, United States
- Savige, Judith A., University of Melbourne, Melbourne, Victoria, Australia
- Lennon, Rachel, The University of Manchester, Manchester, United Kingdom
Group or Team Name
- ClinGen Alport Syndrome Variant Curation Expert Panel.
Background
The ClinGen Alport Syndrome (AS) Variant Curation Expert Panel (VCEP) was established in 2023 with the purview to define variant classification criteria tailored for the genes COL4A3, COL4A4, and COL4A5 in the context of AS and its associated phenotypes. These refined criteria will then be used to determine expert classifications of variant pathogenicity and interpretations of relevance to disease causality. ClinGen VCEPs across other disease areas have demonstrated that this process enhances the accuracy and consistency of variant classification, and can decrease the number of variants that are of uncertain significance.
Methods
Using the 2015 ACMG/AMP Sequence Variant Classification framework as the basis, the AS VCEP is systematically reviewing the 26 defined lines of evidence to determine ways in which they can be refined to be more specific to the known biology of collagen genes and the known characteristics of AS presentations.
Results
The lines of evidence considered in variant classification fall into two main categories: human observational data and predictive and functional data. In refining the use of human observational data-related evidence, the AS VCEP have defined the phenotypes that must be present for an individual to be considered a ‘case’; a concept integral to the application of multiple of these evidence types, and established thresholds to determine whether a variant’s frequency in the population is consistent with disease causality. In reviewing predictive lines of evidence, the AS VCEP is paying particular attention to glycine variants affecting the Gly-X-Y repeat in the triple helical domain, developing guidance for how to appropriately weight the known damaging impact of this established, dominant negative disease mechanism in comparison to other variant types. Finally, recommendations are also being developed to guide calibrated integration of evidence provided by functional assays.
Conclusion
The work of the AS VCEP in developing tailored criteria for the classification of variants in COL4A3, COL4A4, and COL4A5 will provide a harmonized framework that maximizes the utility of available evidence, leading to improved accuracy in variant classification and interpretation, in turn, improving clinical care for individuals with variants in these genes.
Funding
- Other NIH Support