ClinVar Miner

Submissions for variant NM_201253.3(CRB1):c.2506C>A (p.Pro836Thr) (rs116471343)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414087 SCV000490510 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing The P836T variant in the CRB1 gene has been reported previously in association with autosomal recessive retinitis pigmentosa (RP), cystoid macular edema with moderately decreased cone function, or early onset retinal dystrophy when present in the homozygous state or with a second variant detected in the CRB1 gene; however, in vitro functional studies were not included (Henderson et al., 2011; Bujakowska et al., 2012; Wolfson et al., 2015) Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports P836T was observed in 12/4406 (0.27%) alleles from individuals of African American background, indicating it may be a rare variant in this population. The P836T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P836T as a variant of uncertain significance.
Mendelics RCV000986491 SCV001135503 pathogenic Leber congenital amaurosis 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001064315 SCV001229208 pathogenic Retinitis pigmentosa 12; Leber congenital amaurosis 8 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 836 of the CRB1 protein (p.Pro836Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs116471343, ExAC 0.2%). This variant has been observed in individuals affected with retinitis pigmentosa or early-onset rod/cone dystrophy (PMID: 28819299, 20956273, 22065545, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372352). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001073689 SCV001239248 pathogenic Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284928 SCV001471027 likely pathogenic none provided 2019-12-10 criteria provided, single submitter clinical testing The CRB1 c.2506C>A; p.Pro836Thr variant (rs116471343) is reported in the literature in multiple individuals affected with retinal or macular dystrophies (Bujakowska 2012, den Hollander 2004, Henderson 2011, Motta 2017, Wolfson 2015). This variant has been found in affected individuals both in the homozygous state (Bujakowska 2012, Wolfson 2015) and in individuals that carried a second CRB1 variant (Bujakowska 2012, Henderson 2011, Motta 2017). The p.Pro836Thr variant is found in the African population with an overall allele frequency of 0.28% (70/24958 alleles) in the Genome Aggregation Database. The proline at codon 836 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Bujakowska K et al. CRB1 mutations in inherited retinal dystrophies. Hum Mutat. 2012 Feb;33(2):306-15. den Hollander AI et al. CRB1 mutation spectrum in inherited retinal dystrophies. Hum Mutat. 2004 Nov;24(5):355-69. Henderson RH et al. Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. Br J Ophthalmol. 2011 Jun;95(6):811-7. Motta FL et al. The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes. Sci Rep. 2017 Aug 17;7(1):8654. Wolfson Y et al. CRB1-Related Maculopathy With Cystoid Macular Edema. JAMA Ophthalmol. 2015 Nov;133(11):1357-60.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376383 SCV001573503 likely pathogenic Retinitis pigmentosa 12 2021-04-08 criteria provided, single submitter research The CRB1 c.2506C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic.

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