Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001995121 | SCV002255560 | likely pathogenic | Retinitis pigmentosa 12; Leber congenital amaurosis 8 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 450 of the CRB1 protein (p.Cys450Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CRB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1470081). 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 CRB1 protein function with a positive predictive value of 80%. This variant disrupts the p.Cys450 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| 3billion, |
RCV002250793 | SCV002521196 | likely pathogenic | Leber congenital amaurosis 8 | 2024-07-30 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. in silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6); 3Cnet: 0.79 (>=0.6)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CRB1-related disorder (ClinVar ID: VCV001470081). Different missense changes at the same codon (p.Cys450Arg, p.Cys450Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000865858, VCV001068031 / PMID: 33579689). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |