Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001215982 | SCV001387753 | pathogenic | Cone-rod dystrophy 13; Leber congenital amaurosis 6 | 2023-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 800 of the RPGRIP1 protein (p.Glu800Lys). This variant is present in population databases (rs565837539, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 24123792, 26047050, 27422788; 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: 438161). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RPGRIP1 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002230986 | SCV002511857 | likely pathogenic | Leber congenital amaurosis | 2022-04-15 | criteria provided, single submitter | clinical testing | Variant summary: RPGRIP1 c.2398G>A (p.Glu800Lys) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 247938 control chromosomes (gnomAD). c.2398G>A has been reported in the literature in individuals affected with inherited retinal disease, including Leber Congenital Amaurosis and Retinitis Pigmentosa (Neveling_2013, Wang_2015, Turro_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| NIHR Bioresource Rare Diseases, |
RCV000504829 | SCV000599099 | likely pathogenic | Abnormality of the eye | 2015-01-01 | no assertion criteria provided | research | Rare ocular disorder associated to additional undetermined phenotypes |