Submissions for variant NM_020366.4(RPGRIP1):c.2510C>G (p.Ala837Gly)

gnomAD frequency: 0.00008  dbSNP: rs373515194

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001111269	SCV001268815	uncertain significance	Leber congenital amaurosis 6	2017-04-28	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	RCV001111270	SCV001268816	uncertain significance	Cone-rod dystrophy 13	2017-04-28	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.
Invitae	RCV001348556	SCV001542861	uncertain significance	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2022-09-01	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 837 of the RPGRIP1 protein (p.Ala837Gly). This variant is present in population databases (rs373515194, gnomAD 0.009%). This missense change has been observed in individual(s) with glaucoma (PMID: 21224891). ClinVar contains an entry for this variant (Variation ID: 881935). 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. 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	RCV001111269	SCV002045100	uncertain significance	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001111270	SCV002045111	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	RCV002282458	SCV002570918	uncertain significance	not specified	2022-07-14	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1 c.2510C>G (p.Ala837Gly) results in a non-conservative amino acid change located in the 2nd 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 4.8e-05 in 249248 control chromosomes (gnomAD). This frequency is lower than the estimated maximum expected for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (0.0011), allowing no conclusion about variant significance. c.2510C>G has been reported in the literature in heterozygous individuals affected with glaucoma (Fernandez-Martnez_2011) and retinitis pigmentosa, however in the latter case a co-occurring (likely) pathogenic variant in a different gene could explain the phenotype (Eisenberger_2013). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. One of these publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a somewhat decreased protein-interaction with nephrocystin-4 (NPHP4) in a yeast two-hybrid assay (Fernandez-Martnez_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.