Submissions for variant NM_020366.4(RPGRIP1):c.3358A>C (p.Ile1120Leu)

dbSNP: rs137853911

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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, LabCorp	RCV002265931	SCV002547530	uncertain significance	not specified	2024-05-22	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 (IPR041091) 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 estimated 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 (e.g. 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. The following publications have been ascertained in the context of this evaluation (PMID: 30902645, 18055816). ClinVar contains an entry for this variant (Variation ID: 837039). Based on the evidence outlined above, the variant was classified as uncertain significance.