Submissions for variant NM_020366.4(RPGRIP1):c.2512A>G (p.Ile838Val)

gnomAD frequency: 0.00005  dbSNP: rs772480252

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038820	SCV001202318	uncertain significance	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2022-06-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 838 of the RPGRIP1 protein (p.Ile838Val). This variant is present in population databases (rs772480252, gnomAD 0.04%). This missense change has been observed in individual(s) with glaucoma (PMID: 21224891). ClinVar contains an entry for this variant (Variation ID: 837476). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RPGRIP1 function (PMID: 21224891). 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	RCV002222660	SCV002500178	uncertain significance	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1 c.2512A>G (p.Ile838Val) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249240 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.2512A>G has been reported in the literature in individuals affected with glaucoma (Fernandez-Martnez_2011). This report does not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. Fernandez-Martnez_2011 demostrated that this variant reduced interaction of the variant protein with nephrocystin (NPHP4). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.