Submissions for variant NM_201253.3(CRB1):c.3122T>C (p.Met1041Thr)

gnomAD frequency: 0.00001  dbSNP: rs62635656

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV004528086	SCV000914379	pathogenic	CRB1-related disorder	2018-08-09	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the CRB1 c.3122T>C (p.Met1041Thr) missense variant has been reported in at least three studies in which it is found in a homozygous state in total of 37 individuals from two large families, the majority of whom were described as being affected with autosomal recessive retinitis pigmentosa (arRP) (den Hollander et al. 1999; Hettinga et al. 2016; Mathijssen et al. 2016). The p.Met1041Thr variant was also detected in a heterozygous state in six unaffected parents of affected individuals. An additional individual with arRP was reportedly heterozygous for the p.Met1041Thr but also carried likely causative variants in other genes associated with arRP (Eisenberger et al. 2013). To date, this variant has not been reported in association with autosomal dominant retinal disorders or other autosomal recessive phenotypes. The p.Met1041Thr variant was reported in a heterozygous state in 16 of 940 controls and is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Met1041Thr variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045972	SCV001209849	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2023-07-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met1041 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 10508521, 30543658), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 5730). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 10508521, 27380427). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs62635656, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1041 of the CRB1 protein (p.Met1041Thr).
Blueprint Genetics	RCV001075294	SCV001240910	pathogenic	Retinal dystrophy	2017-11-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001250615	SCV004180122	pathogenic	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450614	SCV004180123	pathogenic	Pigmented paravenous retinochoroidal atrophy	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000006084	SCV004180124	pathogenic	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250615	SCV004211249	pathogenic	Leber congenital amaurosis 8	2024-03-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075294	SCV005071500	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001075294	SCV005185921	pathogenic	Retinal dystrophy	2024-05-03	criteria provided, single submitter	clinical testing	Variant summary: CRB1 c.3122T>C (p.Met1041Thr) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251068 control chromosomes. c.3122T>C has been reported in the literature in multiple individuals affected with Retinal Dystrophy (Mathijssen_2017, DenHollander_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10508521, 27380427). ClinVar contains an entry for this variant (Variation ID: 5730). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005007827	SCV005637527	pathogenic	Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-06-04	criteria provided, single submitter	clinical testing
OMIM	RCV000006084	SCV000026266	pathogenic	Retinitis pigmentosa 12	1999-10-01	no assertion criteria provided	literature only
Retina International	RCV000086336	SCV000118482	not provided	not provided		no assertion provided	not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250615	SCV001425484	pathogenic	Leber congenital amaurosis 8		no assertion criteria provided	research