ABCA4 p.Arg653His

The NM_000350.3:c.1958G>A variant in ABCA4 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 653 (p.Arg653His). The total minor allele frequency in gnomAD v4.1.0 is 0.00001488 (24/1612788 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.889 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The OR is 32.8 and the CI is 9.71- 141.13, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in at least 3 individuals with ABCA4-related retinopathy. Of those individuals, one individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant which was confirmed in trans by parental/family testing (PM3; PMID:23776498). Another missense variant, c.1957C>T; p.Arg653Cys, in the same codon has been classified as pathogenic for ABCA4-related retinopathy by the ClinGen ABCA4 VCEP (PM5). ATPase activity in HEK293 cells showed ATPase activity similar to and above 80% of wildtype ABCA4 indicating that this variant does not impact protein function (BS3_Supporting; PMID:33375396). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence points [11pts -1pt (BS3_S) = 10 pts] are still consistent with a pathogenic classification. ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PS4, PP3_Moderate, PM3, PM5, PM2_Supporting, BS3_Supporting.