Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000421632 | SCV000511908 | likely pathogenic | not provided | 2015-05-07 | criteria provided, single submitter | clinical testing | The Y1858N variant that is likely pathogenic in the ABCA4 gene has not been reported as a pathogenic variant nor as a benign polymorphism to our knowledge. The Y1858N was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI ESP Exome Sequencing Project. This variant has been seen at GeneDx in another patient referred for the Stargardt disease panel analysis. The Y1858N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, another missense variant, a non-conservative substitution, at this residue (Y1858D) has been reported in association with Stargardt disease (Oldani et al., 2012). Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded. |
| Invitae | RCV000421632 | SCV001559205 | pathogenic | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1858 of the ABCA4 protein (p.Tyr1858Asn). This variant is present in population databases (rs371489809, gnomAD 0.002%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 28446513; Invitae). 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: 377406). 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%. For these reasons, this variant has been classified as Pathogenic. |
| MGZ Medical Genetics Center | RCV002289547 | SCV002579835 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2021-12-03 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002480281 | SCV002794130 | likely pathogenic | Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 | 2021-10-13 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV003224874 | SCV003921098 | likely pathogenic | Age related macular degeneration 2 | 2023-03-06 | criteria provided, single submitter | clinical testing | _x000D_ Criteria applied: PM1, PM3, PM5, PM2_SUP, PP3 |