ClinVar Miner

Submissions for variant NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr) (rs62645748)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000086331 SCV000343269 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing
Invitae RCV000554663 SCV000650638 pathogenic Retinitis pigmentosa 12; Leber congenital amaurosis 8 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 948 of the CRB1 protein (p.Cys948Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant also falls at the first nucleotide of exon 9 of the CRB1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs62645748, ExAC 0.03%). This variant has been reported in many families and individuals affected with Leber congenital amaurosis, early-onset retinal dystrophy, and retinitis pigmentosa and is considered one of the most common causes of disease (PMID: 10508521, 19401883, 18055816, 23379534, 27113771, 24512366, 20956273). ClinVar contains an entry for this variant (Variation ID: 39614). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762874 SCV000893254 pathogenic Pigmented paravenous chorioretinal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778211 SCV000914377 pathogenic CRB1-Related Disorders 2018-12-04 criteria provided, single submitter clinical testing The CRB1 c.2843G>A (p.Cys948Tyr) missense variant is described as the most common variant in individuals with Leber congenital amaurosis (LCA), detected in approximately 20% of probands (Weleber et al 2013). The p.Cys948Tyr variant has been reported in at least four studies in a total of 36 probands with either LCA or retinitis pigmentosa, including in six probands in a homozygous state, in 25 in a compound heterozygous state and in five in a heterozygous state with an unidentified second variant (den Hollander et al. 1999; Lotery et al. 2001; Henderson et al. 2011; Corton et al. 2013). The p.Cys948Tyr variant was absent from 240 unaffected control individuals and is reported at a frequency of 0.000397 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Cys948Tyr 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.
OMIM RCV000032814 SCV000056582 pathogenic Leber congenital amaurosis 8 2001-03-01 no assertion criteria provided literature only
OMIM RCV000032815 SCV000056583 pathogenic Retinitis pigmentosa 12 2001-03-01 no assertion criteria provided literature only
GeneReviews RCV000032814 SCV000087117 pathologic Leber congenital amaurosis 8 2013-05-02 no assertion criteria provided curation Converted during submission to Pathogenic.
Retina International RCV000086331 SCV000118477 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505155 SCV000598920 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787579 SCV000926559 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research

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