Submissions for variant NM_201253.3(CRB1):c.2234C>T (p.Thr745Met)

gnomAD frequency: 0.00003  dbSNP: rs28939720

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000809110	SCV000949250	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 745 of the CRB1 protein (p.Thr745Met). This variant is present in population databases (rs28939720, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa and/or Leber congenital amaurosis (PMID: 10508521, 15024725, 20956273, 23449718, 24715753). 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: 5733). 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 with a positive predictive value of 80%. This variant disrupts the p.Thr745 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 10508521, 15024725, 20956273, 22968130, 23449718, 24715753), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074789	SCV001240385	pathogenic	Retinal dystrophy	2019-06-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086315	SCV001248711	pathogenic	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196030	SCV001366459	pathogenic	Pigmented paravenous retinochoroidal atrophy	2019-02-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000086315	SCV001905665	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000787576	SCV001950245	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Thr745Met 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, PP3, PM3-S, PM1, PP1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
GeneDx	RCV000086315	SCV001983155	pathogenic	not provided	2023-06-13	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: 28460491, 28341475, 32531858, 31725702, 28600779, 24715753, 23590195, 18723146, 20079931, 23105016, 21151602, 20956273, 23362850, 29869924, 28559085, 32176805, 31589614, 33576794, 33090715, 33029571, 33342761, 33077954, 35119454, 31879567, 34884448, 10508521)
3billion	RCV001250601	SCV002058771	likely pathogenic	Leber congenital amaurosis 8	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005733, PMID:10508521, PS1_S). A different missense change at the same codon has been reported to be associated with CRB1 related disorder (ClinVar ID: VCV000973910,VCV000973930, PMID:22968130, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.807, 3CNET: 0.984, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000064, PM2_M). Each parent is heterozygous for the variant (PM3_P, 3billion dataset). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Mendelics	RCV001196030	SCV002519442	pathogenic	Pigmented paravenous retinochoroidal atrophy	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496280	SCV002808755	pathogenic	Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8	2022-05-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001250601	SCV004180021	likely pathogenic	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001196030	SCV004180022	likely pathogenic	Pigmented paravenous retinochoroidal atrophy	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000006087	SCV004180023	likely pathogenic	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250601	SCV004211110	pathogenic	Leber congenital amaurosis 8	2023-10-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000006087	SCV004804944	pathogenic	Retinitis pigmentosa 12	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000006087	SCV000026269	pathogenic	Retinitis pigmentosa 12	1999-10-01	no assertion criteria provided	literature only
Retina International	RCV000086315	SCV000118461	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787576	SCV000926556	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250601	SCV001425469	pathogenic	Leber congenital amaurosis 8		no assertion criteria provided	research
Faculty of Health Sciences, Beirut Arab University	RCV001257864	SCV001434711	pathogenic	Autosomal recessive retinitis pigmentosa	2012-10-26	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000086315	SCV001921834	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086315	SCV001955174	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086315	SCV001968241	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826422	SCV002090164	pathogenic	Leber congenital amaurosis	2020-12-21	no assertion criteria provided	clinical testing