Compendium of Clinical Variant Classification for 2,246 Unique ABCA4 Variants to Clarify Variant Pathogenicity in...

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Biallelic variants in the ABCA4 gene are the primary cause of Stargardt disease (STGD1), the most common inherited macular disorder.
• Classifying ABCA4 variants is complex due to numerous variants, rare alleles, complex alleles lacking phasing data, variable expressivity, and reduced penetrance of hypomorphic variants, leading to many variants of uncertain significance.

Purpose of the Study:

• To reclassify the pathogenicity of variants within the ABCA4 gene.
• To enhance the accuracy of diagnosis and genetic counseling for inherited retinal diseases associated with ABCA4 variants.

Main Methods:

• Compiled data from approximately 11,000 probands with ABCA4-associated inherited retinal diseases from literature up to 2020.
• Adapted ACMG/AMP classification guidelines, incorporating ClinGen recommendations, for ABCA4 variants.
• Applied these classifications to all 2,246 unique variants in the ABCA4 Leiden Open Variation Database (LOVD).

Main Results:

• Successfully assigned pathogenicity classifications to 2,246 unique ABCA4 variants.
• 1,248 variants were classified as likely pathogenic or pathogenic.
• 194 variants were classified as likely benign or benign.

Conclusions:

• This comprehensive reclassification of ABCA4 variants, based on the largest dataset to date, provides a more accurate understanding of variant pathogenicity.
• The improved classification system will significantly aid in the diagnosis and genetic counseling of individuals affected by ABCA4-associated retinopathy.
• This structured approach addresses the challenges in ABCA4 variant interpretation, benefiting clinical practice and patient care.