Submissions for variant NM_201253.3(CRB1):c.2042G>A (p.Cys681Tyr)

dbSNP: rs62636266

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046839	SCV001210757	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 681 of the CRB1 protein (p.Cys681Tyr). This variant is present in population databases (rs62636266, gnomAD 0.0009%). This missense change has been observed in individual(s) with CRB1-related conditions (PMID: 17525851, 24265693, 30576320, 32865313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99874). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CRB1 protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000086312	SCV001248709	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000086312	SCV001905546	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453016	SCV004179998	pathogenic	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453015	SCV004179999	pathogenic	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003453016	SCV004211182	pathogenic	Leber congenital amaurosis 8	2023-06-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815176	SCV005069231	likely pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004815176	SCV005885694	pathogenic	Retinal dystrophy	2025-02-26	criteria provided, single submitter	clinical testing	Variant summary: CRB1 c.2042G>A (p.Cys681Tyr) results in a non-conservative amino acid change in 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 4e-06 in 251086 control chromosomes. c.2042G>A has been reported in the literature in multiple individuals affected with Leber congenital amaurosis (examples: Lotery_2001, Preising_2007, Eisenberger_2013, Weisschuh_2018, Sallum_2020, Skorczyk-Werner_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: 17525851, 30576320, 24265693, 32865313, 11231775, 36369640). ClinVar contains an entry for this variant (Variation ID: 99874). Based on the evidence outlined above, the variant was classified as pathogenic.
Retina International	RCV000086312	SCV000118458	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001831900	SCV002090158	likely pathogenic	Leber congenital amaurosis	2020-11-04	no assertion criteria provided	clinical testing