Submissions for variant NM_020366.4(RPGRIP1):c.1904C>G (p.Ala635Gly)

gnomAD frequency: 0.00012  dbSNP: rs200325360

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000276189	SCV000334720	uncertain significance	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069833	SCV001235030	uncertain significance	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 635 of the RPGRIP1 protein (p.Ala635Gly). This variant is present in population databases (rs200325360, gnomAD 0.03%). This missense change has been observed in individual(s) with glaucoma (PMID: 21224891). ClinVar contains an entry for this variant (Variation ID: 282963). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RPGRIP1 protein function with a positive predictive value of 80%. 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.
Genome-Nilou Lab	RCV001800644	SCV002044945	uncertain significance	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001800645	SCV002044956	uncertain significance	Cone-rod dystrophy 13	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488496	SCV004241292	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1 c.1904C>G (p.Ala635Gly) results in a non-conservative amino acid change located in the RPGR-interacting protein 1, first C2 domain (IPR021656) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249308 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1904C>G has been reported in the literature in heterozygous individuals affected with normal tension glaucoma and primary open angle glaucoma (e.g. Fernandez-Martinez_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. One publication reports experimental evidence evaluating an impact on protein function showing reduced interaction with C2 domain partner NPHP4 in a yeast-two-hybrid assay, however, does not allow convincing conclusions about the variant effect (e.g. Fernandez-Martinez_2011). The following publication has been ascertained in the context of this evaluation (PMID: 21224891). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.