Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485764 | SCV000564530 | likely pathogenic | not provided | 2014-05-27 | criteria provided, single submitter | clinical testing | A novel I1130T variant that is likely pathogenic was identified in theABCA4 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The I1130T variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The 1130T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G1127E, R1129C, R1129H and I1133T) have been reported in the Human Gene Mutation Database in association with Stargardt disease, age-related macular degeneration, and retinal disease (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. |
| Invitae | RCV000485764 | SCV003523420 | pathogenic | not provided | 2022-03-18 | criteria provided, single submitter | clinical testing | 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417988). This missense change has been observed in individual(s) with Stargardt disease (PMID: 26780318, 29925512). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1130 of the ABCA4 protein (p.Ile1130Thr). |