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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 many rare ABCA4 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 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 incorporating ClinGen recommendations and assigned these classifications to all 2,246 unique variants from the ABCA4 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 ABCA4-associated retinopathy cases so far, will improve both the diagnosis as well as genetic counselling for individuals with ABCA4-associated retinopathy.<\/jats:p>","DOI":"10.1155\/2023\/6815504","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T12:05:06Z","timestamp":1703592306000},"page":"1-12","source":"Crossref","is-referenced-by-count":20,"title":["Compendium of Clinical Variant Classification for 2,246 Unique ABCA4 Variants to Clarify Variant Pathogenicity in Stargardt Disease Using a Modified ACMG\/AMP Framework"],"prefix":"10.1155","volume":"2023","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-927X","authenticated-orcid":true,"given":"St\u00e9phanie S.","family":"Cornelis","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0402-9006","authenticated-orcid":true,"given":"Miriam","family":"Bauwens","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-0797","authenticated-orcid":true,"given":"Lonneke","family":"Haer-Wigman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6636-5537","authenticated-orcid":true,"given":"Marieke","family":"De Bruyne","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1013-1717","authenticated-orcid":true,"given":"Madhulatha","family":"Pantrangi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"PreventionGenetics (a Division of Exact Sciences), Marshfield, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5609-6895","authenticated-orcid":true,"given":"Elfride","family":"De Baere","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3015-3545","authenticated-orcid":true,"given":"Robert B.","family":"Hufnagel","sequence":"additional","affiliation":[{"name":"Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-4124","authenticated-orcid":true,"given":"Claire-Marie","family":"Dhaenens","sequence":"additional","affiliation":[{"name":"Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4954-5592","authenticated-orcid":true,"given":"Frans P. M.","family":"Cremers","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-236"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1080\/13816810.2021.1913610"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-24636-1"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1111\/aos.14996"},{"key":"5","first-page":"135","article-title":"Fundus flavimaculatus","volume-title":"Retinal Dystrophies and Degenerations","author":"P. 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