ClinVar Genomic variation as it relates to human health

This variant has been observed, either as homozygous (Hwang JC et al., 2009) or compound heterozygous (Lewis RA et al., 1999) in individuals who have been diagnosed with Stargardt disease. It co-segregates with disease and was found in trans with the known pathogenic variant, G1961E (Duncker T et al., 2015). In the protein, it is present in the helical transmembrane domain 7 and is close to the nucleotide binding domain-1. Studies in HEK 293 cells showed that, compared with wild-type, the protein yield and ATP-binding capacity of this variant was reduced (Sun H et al., 2000). Finally, multiple computational algorithms predict this variant to be deleterious and its frequency in the population databases (1000 Genomes, Exome Sequencing Project [ESP] and ExAC) is either absent or very low. Therefore, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.

The ABCA4 c.4139C>T (p.Pro1380Leu) missense variant has been reported in at least ten studies in which it is found in at least 38 individuals with either Stargardt disease (STGD), cone-rod dystrophy or age related macular degeneration including in five individuals in a homozygous state, at least 29 in a compound heterozygous state, and four individuals in a heterozygou state (Shroyer et al. 1999; Lewis et al. 1999; Shroyer et al. 2001; Briggs et al. 2001; Oh et al. 2004; Fingert et al. 2006; Hwang et al. 2009; Cideciyan et al. 2009; Chacón-Camacho et al. 2013; Duncker et al. 2015). The p.Pro1380Leu variant has been shown to segregate with STGD disease in at least three families (Lewis et al. 1999; Shroyer et al. 2001; Cideciyan et al. 2009). The variant has not been reported in association with retinitis pigmentosa. The p.Pro1380Leu variant was absent from at least 895 controls and is reported at a frequency of 0.001973 in the Ashkenazi Jewish population of the Genome Aggregation Database. In vitro analysis in HEK-293 cells demonstrated that the p.Pro1380Leu variant resulted in reduced expression of the protein and defective ATP binding (Sun et al. 2000). Based on the collective evidence, the p.Pro1380Leu variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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: 26766544, 28559085, 29925512, 31429209, 32531858, 33706644, 34315337, 35456422, 33369172, 32037395, 25283059, 15579991, 9973280, 25087612, 11527935, 28341476, 28041643, 19074458, 10396622, 16682602, 30634128, 30204727, 30718709, 11017087, 32467599, 31456290, 32581362, 33375396, 34426522, 31573552, 31589614, 32619608, 27030965, 28947085, 35119454)

Clinical significance based on ACMG v2.0

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1380 of the ABCA4 protein (p.Pro1380Leu). This variant is present in population databases (rs61750130, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0108 - This gene is known to be associated with both recessive and dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 28). 0304 - Variant is present in gnomAD <0.01 for recessive indication (66 heterozygotes, 0 homozygotes) 0501 - Missense variant consistently predicted to be damaging by in-silico tools or highly conserved with a major amino acid change. 0604 - Variant is not located in an established domain, motif or hotspot. 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously described as pathogenic in multiple individuals (PMID: ClinVar, 11726554, 28947085) 1002 - Moderate functional evidence supporting abnormal protein function. Functional analysis demonstrated that the variant resulted in reduced expression of the protein and defective ATP binding (PMID: 11017087) 1205 - Variant is maternally inherited.

The ABCA4 c.4139C>T variant is predicted to result in the amino acid substitution p.Pro1380Leu. This variant has been reported many times in the homozygous and compound heterozygous states in individuals with ABCA4-related retinal disease (see for examples: Lewis et al. 1999. PubMed ID: 9973280; Oh et al. 2004. PubMed ID: 15579991; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, indicating it is relatively common in this population. This variant is interpreted as pathogenic.