Table 1.

Summary of ABCA4 Variant Severity Clarification System as Proposed by Lee et al²⁷

Severity Level	Summary of Classification System
Null or loss-of-function variants (PVS1)	Variant is expected to result in null alleles, such as nonsense, frameshifts, canonical ± 1 or 2 splice sites, large multi-exon deletions. These variants skewed toward the most severe clinical phenotypes, and were found to be at a lower-than-expected proportion
Severe	Variants were classified as severe if they were: (1)Observed as the causal allele in trans with hypomorphic alleles (2)Validated by functional studies, where these variants are shown to significantly reduce ABCA4 expression and basal ATPase activity in HEK293T and patient-derived cell lines (3)Frequently identified in compound heterozygous and/or homozygous state in patients with a poor disease prognosis
Moderate	These variants were proposed to have a partial reduction in expression and basal ATPase activity. Variants were classified as moderate if: (1)There is no intrinsic evidence of severity in their effect on ABCA4 protein function (2)Functional studies indicate a moderate impact (3)The clinical association is still undetermined
Mild and hypomorphic variants	These variants exhibit expression and functional properties similar to the normal ABCA4 protein, and were proposed to be associated with a milder prognosis. Hypomorphic variants were proposed to be pathogenic only when paired with a more severe variant on the other chromosome. This class was divided into three groups: (1)The primary disease-causing variant c.5882G>A (p.Gly1961Glu) (2)The common hypomorphic allele c.5603A>T (p.Asn1868Ile) (3)A group of other rare hypomorphic variants, which were associated with mild disease prognosis