ClinVar Miner

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

gnomAD frequency: 0.00012  dbSNP: rs200325360
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Total submissions: 5
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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
Invitae RCV001069833 SCV001235030 uncertain significance Cone-rod dystrophy 13; Leber congenital amaurosis 6 2022-08-04 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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