Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000778262 | SCV000914434 | likely pathogenic | ABCA4-Related Disorders | 2017-04-27 | criteria provided, single submitter | clinical testing | Across a selection of the available literature, the ABCA4 c.1805G>A (p.Arg602Gln) missense variant has been reported in a total of seven individuals with Stargardt disease including in one in a homozygous state, four in a compound heterozygous state, and two in a heterozygous state in whom a second variant has not been identified (Briggs et al. 2001; Webster et al. 2001; Ernest et al. 2009; Burke et al. 2010; Zernant et al. 2011; Fujinami et al. 2013; Gemenetzi et al. 2013). The authors suggested the presence of the variant in a heterozygous state in patients may be attributed to the large size and allelic heterogeneity of the ABCA4 gene. Overlapping phenotypes with other ABCA4 associated diseases such as cone-rod dystrophy, dominant forms of macular deneration, and retinitis pigmentosa may also complicate the identification of disease-causing ABCA4 variants. The p.Arg602Gln variant was absent from at least 96 controls and is reported at a frequency of 0.00023 in the African American population of the Exome Sequencing Project, but this is based on one allele in an area of good coverage so the variant is presumed to be rare. The variant is significantly over-represented in the affected population, and is likely contributing to disease. Based on the evidence, the p.Arg602Gln 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. |
| Invitae | RCV000085429 | SCV001384709 | pathogenic | not provided | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 602 of the ABCA4 protein (p.Arg602Gln). This variant is present in population databases (rs61749410, gnomAD 0.008%). This missense change has been observed in individuals with retinal disease (PMID: 20696155, 22449572, 23982839, 25472526, 25910913). ClinVar contains an entry for this variant (Variation ID: 99085). 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.Arg602 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16103129, 23755871). 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. |
| Retina International | RCV000085429 | SCV000117566 | not provided | not provided | no assertion provided | not provided |