Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001038290 | SCV001201754 | uncertain significance | Cone-rod dystrophy 13; Leber congenital amaurosis 6 | 2022-04-25 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1120 of the RPGRIP1 protein (p.Ile1120Leu). This variant is present in population databases (rs137853911, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RPGRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 837039). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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, |
RCV002265931 | SCV002547530 | uncertain significance | not specified | 2022-05-18 | criteria provided, single submitter | clinical testing | Variant summary: RPGRIP1 c.3358A>C (p.Ile1120Leu) results in a conservative amino acid change located in the RPGRIP1, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.3358A>C has been reported in the literature in individuals affected with retinitis pigmentosa (Vallespin_2007, Martin-Merida_2019). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. 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 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |