Compendium of clinical variant classification for 2,247 uniqueABCA4variants 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.

Quantification of Fundus Autofluorescence Features in a Molecularly Characterized Cohort of More Than 3500 Inherited Retinal Disease Patients from the United Kingdom

“…We also applied AIRDetect to monitor progression in patients belonging to three subgroups of ABCA4 (Figure 6). Patients were classified into three groups (A, B and C) based on increasing severity of genetic variants as defined by Cornelis et al 20,21 . Patients in group A had two severe variants, while group C had a mild variant in trans with any other variant.…”

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes

“…In this proband, this variant was present with a second severe ABCA4 allele; therefore, if confirmed to be in trans , this will provide a genetic explanation for the disease for this patient. Variant c.6817-679C>G was identified in proband 066668, alongside a second ABCA4 DIV c.4539+2028C>T, previously determined to have a moderately severe effect [ 32 , 33 , 34 ]. We already considered a novel homozygous RP1L1 variant resulting in a frameshift (c.1509del; p.(Gly504Alafs*4)) to be the genetic explanation for disease for this patient, but we could not fully exclude the involvement of ABCA4 without further exploration of this novel DIV due to a previous report of an alternate allele, which was splice-altering (c.6817-679C>A, p.Gln2272_Asp2273fs*10, r.[=,6816_6817ins6816+1_6817-682]) (SpliceAI delta scores: AG 0.70, DG 0.91) [ 35 ].…”

Stargardt disease-associated missense and synonymous ABCA4 variants result in aberrant splicing

“…The updated RNA and protein products have been deposited into the LOVD database for ABCA4 ( www.lovd.nl/ABCA4 ). Moreover, the table reports their ACMG/AMP classification according to the previously published studies ( 22 ), as well as their updated ACMG/AMP classification, taking into account the impact on splicing reported in this study. It is important to note that, out of 18 investigated missense variants, the ACMG/AMP classification of four variants was raised to a higher severity class, indicating increased reliability of their pathogenic nature.…”

“…Updating the ACMG/AMP classification of the variants reported in this study was conducted by referencing the previous comprehensive categorization of ABCA4 variants carried out by Cornelis and colleagues ( 22 ). Specifically, Cornelis et al .…”