Compendium of Clinical Variant Classification for 2,246 Unique Variants to Clarify Variant Pathogenicity in Stargardt Disease Using a Modified ACMG/AMP Framework.

Biallelic variants in cause Stargardt disease (STGD1), the most frequent heritable macular disease. Determination of the pathogenicity of variants in proves to be difficult due to (1) the high number of benign and pathogenic variants in the gene; (2) the presence of many rare variants; (3) the presence of complex alleles for which phasing data are absent; (4) the extensive variable expressivity of this disease and (5) reduced penetrance of hypomorphic variants. Therefore, the classification of many variants in is currently of uncertain significance. Here, we complemented the Leiden Open Variation Database (LOVD) with data from ~11,000 probands with -associated inherited retinal diseases from literature up to the end of 2020. We carefully adapted the ACMG/AMP classifications to incorporating ClinGen recommendations and assigned these classifications to all 2,246 unique variants from the LOVD to increase the knowledge of pathogenicity. In total, 1,248 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 -associated retinopathy cases so far, will improve both the diagnosis as well as genetic counselling for individuals with -associated retinopathy.