Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001305369 | SCV001494700 | uncertain significance | Cone-rod dystrophy 13; Leber congenital amaurosis 6 | 2022-09-13 | criteria provided, single submitter | clinical testing | This variant, c.3835_3837del, results in the deletion of 1 amino acid(s) of the RPGRIP1 protein (p.Glu1279del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759881017, gnomAD 0.09%). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 11528500, 29844330). ClinVar contains an entry for this variant (Variation ID: 99824). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RPGRIP1 function (PMID: 15800011, 23213406). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265604 | SCV002547529 | uncertain significance | not specified | 2022-05-26 | criteria provided, single submitter | clinical testing | Variant summary: RPGRIP1 c.3835_3837delGAG (p.Glu1279del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.00015 in 245918 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (0.00015 vs 0.0011), allowing no conclusion about variant significance. c.3835_3837delGAG has been reported in the literature in the heterozygous state in an individual affected with Leber Congenital Amaurosis whose affected cousin did not carry the variant (Gerber_2001). Additionally, the variant was reported in the heterozygous state in a patient with LCA who carried other potentially causitive mutations in GUCY2D (Hosono_2018). These clinical findings indicate the variant may not be associated with the disease. Functional studies have shown the variant to cause a significant enhancement of the interaction of RID with RPGR, an interaction highly resistant to stress stimuli, suggesting gain-of-function effect (Lu_2005). A second study reported the variant to not affect its co-localization with PGR119 or RPGRORF15, nor cause aggregation of mutant RPGRIP1a1 upon co-expression with either of the RPGR isoforms (Patil_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. |
| OMIM | RCV002225082 | SCV000025455 | pathogenic | Leber congenital amaurosis 6 | 2005-05-15 | no assertion criteria provided | literature only | |
| Retina International | RCV000086255 | SCV000118401 | not provided | not provided | no assertion provided | not provided |