Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001379460 | SCV001577263 | pathogenic | Retinitis pigmentosa 12; Leber congenital amaurosis 8 | 2023-06-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1068031). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs746597173, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 450 of the CRB1 protein (p.Cys450Tyr). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230670 | SCV003928746 | uncertain significance | not specified | 2023-04-24 | criteria provided, single submitter | clinical testing | Variant summary: CRB1 c.1349G>A (p.Cys450Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251420 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1349G>A has been reported in the literature in an individual reportedly affected with congenital amaurosis (example: Talib_2022). This report does not provide unequivocal conclusions about association of the variant with Retinal Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |