ClinVar Genomic variation as it relates to human health

ABCA4: PM3:Strong, PM2, PS3:Supporting

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099321, PMID:10958761, PS1_S). 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 (PM3_S). A different missense change at the same codon has been reported to be associated with ABCA4 related disorder (PMID:26161775, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.685, 3CNET: 0.955, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: ABCA4 c.4793C>A (p.Ala1598Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250090 control chromosomes (gnomAD). c.4793C>A has been reported in the literature in multiple individuals affected with autosomal recessive Stargardt disease (examples: Passerini_2010 and Mejecase_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32783370, 19265867). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate A1598D results in reduced basal activity, supporting a damaging effect (Curtis et al., 2020); This variant is associated with the following publications: (PMID: 27014590, 23105016, 20696155, 10958761, 22025579, 28118664, 29178665, 28365912, 19074458, 25525159, 26103963, 29925512, 28559085, 32845050, 31589614, 32619608, 34426522, 32783370)

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1598 of the ABCA4 protein (p.Ala1598Asp). This variant is present in population databases (rs61750155, gnomAD 0.009%). This missense change has been observed in individual(s) with retinal disease (PMID: 10958761, 19074458, 23105016, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99321). 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%. This variant disrupts the p.Ala1598 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26161775), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The ABCA4 c.4793C>A variant is predicted to result in the amino acid substitution p.Ala1598Asp. This variant was reported, in the homozygous state or in the heterozygous state along with a second probable causative variant, in individuals with autosomal recessive retinal disorders (see, for example, Maugeri et al. 2000. PubMed ID: 10958761; Cideciyan et al. 2008. PubMed ID: 19074458; Burke et al. 2010. PubMed ID: 20696155; Abu-Safieh et al. 2012. PubMed ID: 23105016; Table S1, Stone et al. 2017. PubMed ID: 28559085; Table S1, Fujinami et al. 2018. PubMed ID: 29925512). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.