Submissions for variant NM_201253.3(CRB1):c.135C>G (p.Cys45Trp)

gnomAD frequency: 0.00035  dbSNP: rs145141811

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487047	SCV000564914	uncertain significance	not provided	2016-03-12	criteria provided, single submitter	clinical testing	The C45W variant in the CRB1 gene has been reported previously in the heterozygous state in two individuals with retinitis pigmentosa in whom a second CRB1 pathogenic variant was not identified (Clark et al., 2010; Neveling et al., 2012). The C45W variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. The C45W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C45W as a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV000787828	SCV001257167	uncertain significance	Retinitis pigmentosa	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	RCV001247776	SCV001421219	uncertain significance	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 45 of the CRB1 protein (p.Cys45Trp). This variant is present in population databases (rs145141811, gnomAD 0.07%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 20591486, 22164218, 30718709). ClinVar contains an entry for this variant (Variation ID: 418147). 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 expected to disrupt CRB1 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.
Genome-Nilou Lab	RCV003449162	SCV004178802	uncertain significance	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449163	SCV004178803	uncertain significance	Pigmented paravenous retinochoroidal atrophy	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449161	SCV004178804	uncertain significance	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787828	SCV000926841	likely pathogenic	Retinitis pigmentosa	2018-04-01	flagged submission	research
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252198	SCV001427949	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001275643	SCV001460933	uncertain significance	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000487047	SCV001923924	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487047	SCV001959888	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487047	SCV001968756	uncertain significance	not provided		no assertion criteria provided	clinical testing