Submissions for variant NM_201253.3(CRB1):c.1438T>C (p.Cys480Arg)

gnomAD frequency: 0.00006  dbSNP: rs62636264

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086308	SCV000883682	pathogenic	not provided	2017-06-07	criteria provided, single submitter	clinical testing	The CRB1 c.1438T>C;p.Cys480Arg variant has been published in the medical literature in individuals with a clinical diagnosis of Leber congenital amaurosis (Lotery 2001, Stone 2007). This variant is listed in the ClinVar database (Variation ID: 99870) and the dbSNP variant database (rs62636264) with an allele frequency of 0.001082 percent (3/277216 alleles) in the Genome Aggregation Database. This variant occurs in an EGF domain, which contains highly conserved cysteine residues and substitutions in the cysteine residues is likely to result in protein misfolding and other variants altering a cysteine residue in the EGF domains are predicted to be pathogenic (Davis 2007). Accordingly, the cysteine at this position is highly conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Davis JA et al. The N1317H substitution associated with Leber congenital amaurosis results in impaired interdomain packing in human CRB1 epidermal growth factor-like (EGF) domains. J Biol Chem. 2007 Sep 28;282(39):28807-14. Lotery AJ et al. Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch Ophthalmol. 2001 Mar;119(3):415-20. Stone EM. Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 2007 Dec;144(6):791-811.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797320	SCV000936871	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 480 of the CRB1 protein (p.Cys480Arg). This variant is present in population databases (rs62636264, gnomAD 0.009%). This missense change has been observed in individuals with Leber congenital amaurosis (PMID: 11231775, 21757580, 23847139). ClinVar contains an entry for this variant (Variation ID: 99870). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CRB1 protein function with a positive predictive value of 95%. This variant disrupts the p.Cys480 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 11231775, 23847139), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376374	SCV001573492	likely pathogenic	Retinitis pigmentosa 12	2021-04-08	criteria provided, single submitter	research	The CRB1 c.1438T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PM3. Based on this evidence we have classified this variant as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235040	SCV003934268	pathogenic	Retinal dystrophy	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: CRB1 c.1438T>C (p.Cys480Arg) results in a non-conservative amino acid change located in the EGF like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251442 control chromosomes (gnomAD). c.1438T>C has been reported in the literature in multiple individuals affected with Retinal Dystrophy (examples: Lotery_2001, Aleman_2011,Vargas_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21757580, 11231775, 35318874). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV003453012	SCV004179927	likely pathogenic	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453013	SCV004179928	likely pathogenic	Pigmented paravenous retinochoroidal atrophy	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001376374	SCV004179929	likely pathogenic	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003453012	SCV004211154	pathogenic	Leber congenital amaurosis 8	2024-03-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008010	SCV005636151	pathogenic	Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-02-27	criteria provided, single submitter	clinical testing
Retina International	RCV000086308	SCV000118454	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001826777	SCV002090139	pathogenic	Leber congenital amaurosis	2021-10-06	no assertion criteria provided	clinical testing