Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000486363 | SCV000564519 | likely pathogenic | not provided | 2014-09-04 | criteria provided, single submitter | clinical testing | A novel Y603H variant that is likely pathogenic was identified in the ABCA4 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The Y603H variant was not observed in approximately 6,500 individuals of European and African American ancestry in tan external database, indicating it is not a common benign variant in these populations. The Y603H 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 fully conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G606D, I604S, R602Q, R602W) have been reported in the Human Gene Mutation Database in association with retinal dystrophy and Stargardt 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. |
| Ce |
RCV000486363 | SCV000608482 | pathogenic | not provided | 2018-09-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000486363 | SCV003459772 | pathogenic | not provided | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 603 of the ABCA4 protein (p.Tyr603His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cone-rod dystrophy and/or Stargardt disease (PMID: 29555955, 32531858, 34073554). ClinVar contains an entry for this variant (Variation ID: 417981). 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. |
| Blueprint Genetics | RCV001074372 | SCV001239949 | uncertain significance | Retinal dystrophy | 2019-07-29 | flagged submission | clinical testing |