Submissions for variant NM_201253.3(CRB1):c.2290C>T (p.Arg764Cys)

gnomAD frequency: 0.00004  dbSNP: rs62635654

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Medicine, University of Leeds	RCV000656137	SCV000611556	pathogenic	Macular dystrophy	2017-10-27	criteria provided, single submitter	research
Invitae	RCV001052374	SCV001216583	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 764 of the CRB1 protein (p.Arg764Cys). This variant is present in population databases (rs62635654, gnomAD 0.01%). This missense change has been observed in individual(s) with CRB1-related retinopathy (PMID: 10508521, 11389483, 12700176, 20956273, 24512366, 26047050, 28129017, 28341475). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5732). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074882	SCV001240486	pathogenic	Retinal dystrophy	2019-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086317	SCV001248712	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000086317	SCV001446685	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV001352991	SCV001548082	likely pathogenic	CRB1-related maculopathy	2021-01-30	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000006086	SCV001759998	likely pathogenic	Retinitis pigmentosa 12		criteria provided, single submitter	clinical testing
GeneDx	RCV000086317	SCV001830805	pathogenic	not provided	2022-03-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28129017, 10508521, 20956273, 24512366, 26047050, 27670293, 28341475, 23379534, 29391521, 28559085, 31980526, 31630094, 31589614, 34884448, 31736247, 34426522, 33969091, 34946856, 33546218, 30718709, 32507488)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000787577	SCV001950247	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg764Cys variant in CRB1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, BP4, PP1-M, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Fulgent Genetics, Fulgent Genetics	RCV002496279	SCV002810757	pathogenic	Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8	2021-07-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003447471	SCV004175772	pathogenic	Retinitis pigmentosa-deafness syndrome	2023-03-01	criteria provided, single submitter	clinical testing	The missense variant c.2290C>T (p.Arg764Cys) in the CRB1 gene has been reported previously in a compound heterozygous and homozygous state in individuals affected with Autosomal recessive retinitis pigmentosa. Experimental studies have shown that this missense change affects protein function (den Hollander et al., 1999; Yang et al., 2016). This variant is reported with the allele frequency (0.007%) in the gnomAD and novel in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Arginine at position 764 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg764Cys in CRB1 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001250604	SCV004180027	likely pathogenic	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450615	SCV004180028	likely pathogenic	Pigmented paravenous retinochoroidal atrophy	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000006086	SCV004180029	likely pathogenic	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250604	SCV004211120	pathogenic	Leber congenital amaurosis 8	2024-03-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000086317	SCV004238130	likely pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004540990	SCV004774970	pathogenic	CRB1-related disorder	2023-12-05	criteria provided, single submitter	clinical testing	The CRB1 c.2290C>T variant is predicted to result in the amino acid substitution p.Arg764Cys. This variant has been documented to be causative for autosomal recessive retinitis pigmentosa (RP) and autosomal recessive Leber congenital amaurosis (den Hollander et al. 1999. PubMed ID: 10508521; Wang et al. 2015. PubMed ID: 26047050; Corton et al. 2013. PubMed ID: 23379534).
OMIM	RCV000006086	SCV000026268	pathogenic	Retinitis pigmentosa 12	1999-10-01	no assertion criteria provided	literature only
Retina International	RCV000086317	SCV000118463	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787577	SCV000926557	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250604	SCV001425472	pathogenic	Leber congenital amaurosis 8		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086317	SCV001958962	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086317	SCV001966364	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001250604	SCV002583351	pathogenic	Leber congenital amaurosis 8	2021-12-01	no assertion criteria provided	clinical testing