ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs62635656
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778213 SCV000914379 pathogenic CRB1-Related Disorders 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.
Invitae 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 2021-11-26 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

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