Submissions for variant NM_020366.4(RPGRIP1):c.3358A>G (p.Ile1120Val)

gnomAD frequency: 0.00051  dbSNP: rs137853911

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000086972	SCV001149119	uncertain significance	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV001059148	SCV001223760	uncertain significance	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2022-10-25	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 1120 of the RPGRIP1 protein (p.Ile1120Val). This variant is present in population databases (rs137853911, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RPGRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 100589). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPGRIP1 protein function. 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.
Illumina Laboratory Services, Illumina	RCV001111368	SCV001268918	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.
Illumina Laboratory Services, Illumina	RCV001111369	SCV001268919	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.
Genome-Nilou Lab	RCV001111368	SCV002045481	uncertain significance	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001111369	SCV002045492	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	RCV002281926	SCV002570920	uncertain significance	not specified	2023-03-16	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1 c.3358A>G (p.Ile1120Val) results in a conservative amino acid change located in the C-terminal domain (IPR041091) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 248632 control chromosomes (gnomAD and Dopazo_2016). This frequency is not significantly higher than estimated for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis (0.00043 vs 0.0011), allowing no conclusion about variant significance. c.3358A>G has been reported in the literature as a VUS in settings of multigene panel testing in heterozygous individuals affected by a variety of retinal dystrophies, without strong evidence for causality (e.g. Stone_2007, Vallespin_2007, Song_2011, Wang_2014, Tiwari_2016). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV000086972	SCV000119225	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000086972	SCV001923935	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086972	SCV001975023	uncertain significance	not provided		no assertion criteria provided	clinical testing