Compendium of clinical variant classification for 2,247 unique ABCA4 variants to improve genetic medicine access for Stargardt Disease

Abstract Biallelic variants in ABCA4 cause Stargardt disease (STGD1), the most frequent heritable macular disease. Determination of the pathogenicity of variants in ABCA4 proves to be difficult due to 1) the high number of benign and pathogenic variants in the gene; 2) the presence of complex alleles; 3) the extensive variable expressivity of this disease and 4) reduced penetrance of hypomorphic variants. Therefore, the classification of many variants in ABCA4 is currently of uncertain significance. Here we complemented the ABCA4 Leiden Open Variation Database (LOVD) with data from ∼11,000 probands with ABCA4 -associated inherited retinal diseases from literature up to the end of 2020. We carefully adapted the ACMG/AMP classifications to ABCA4 and assigned these classifications to all 2,247 unique variants from the ABCA4 LOVD to increase the knowledge of pathogenicity. In total, 1,247 variants were categorized with a Likely Pathogenic or Pathogenic classification, whereas 194 variants were categorized with a Likely Benign or Benign classification. This uniform and improved structured reclassification, incorporating the largest dataset of ABCA4 -associated retinopathy cases so far, will improve both the diagnosis as well as genetic counselling for individuals with ABCA4 -associated retinopathy.