Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + Homozygous allele count is less than 0 in gnomAD exomes and genomes (PM2). Other variant at this amino acid residue has been classified as pathogenic (PM5, p.Arg24Gly). REVEL score 0.811 (PP3_mod)

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23419329, 11726554, 27820952, 34426522, 29162642, 31180159, 31015497, 9973280, 33261146, 31980526, 32307445, 36672815, 38219857, 23953153, 38540785, 36335097, 38984108, 35120629, 31429209, 33301772, 33608557, 38066771)

Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.81 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000099498 /PMID: 9973280)and different missense changes at the same codon (p.Arg24Cys, p.Arg24Gly / ClinVar ID: VCV000099497, VCV000857107 / PMID: 15494742) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 9973280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;For recessive disorders, detected in trans with a pathogenic variant.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.