Submissions for variant NM_020366.4(RPGRIP1):c.2555G>A (p.Arg852Gln)

gnomAD frequency: 0.00076  dbSNP: rs181758389

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082000	SCV000113935	uncertain significance	not provided	2017-11-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002311	SCV001160204	uncertain significance	not specified	2019-01-24	criteria provided, single submitter	clinical testing	The RPGRIP1 c.2555G>A; p.Arg852Gln variant (rs181758389) is reported in the medical literature in two individuals with early-onset retinal disease (Astuti 2015, Vallespin 2007). However, one of these individuals also carried 2 GUCY2D variants (Astuti 2015). The variant has also been detected at approximately the same frequency in individuals with open angle glaucoma as control individuals (Fernandez 2011). The variant is described in the ClinVar database (Variation ID: 95948) and in the general population with an allele frequency of 0.08% (225/280646 alleles including 2 homozygotes) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. In support of this prediction, in vitro experiments show this variant does not affect interactions of this protein with NPHP (Roepman 2005). Although there are indications this variant may be benign, the clinical significance of this variant is uncertain at this time. References: Astuti GD et al. Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark. Eur J Hum Genet. 2016 Jul;24(7):1071-9. Fernandez-Martinez L et al. Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma. Eur J Hum Genet. 2011 Apr;19(4):445-51. Roepman R et al. Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18520-5. Vallespin E et al. Mutation screening of 299 Spanish families with retinal dystrophies by Leber congenital amaurosis genotyping microarray. Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5653-61.
Illumina Laboratory Services, Illumina	RCV001111273	SCV001268819	uncertain significance	Cone-rod dystrophy 13	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001111274	SCV001268820	uncertain significance	Leber congenital amaurosis 6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001513784	SCV001721466	benign	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2024-01-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001111274	SCV002046067	likely benign	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001111273	SCV002046078	likely benign	Cone-rod dystrophy 13	2021-11-07	criteria provided, single submitter	clinical testing