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

gnomAD frequency: 0.00096  dbSNP: rs116471343

Total submissions: 8

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	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 836 of the CRB1 protein (p.Pro836Thr). This variant is present in population databases (rs116471343, gnomAD 0.3%). This missense change has been observed in individual(s) with retinitis pigmentosa or early-onset rod/cone dystrophy (PMID: 20956273, 22065545, 28819299; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372352). 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%. 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	RCV001810876	SCV001471027	likely pathogenic	not 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137989	SCV003807759	pathogenic	Pigmented paravenous retinochoroidal atrophy	2023-01-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM3 very strong, PP1 supporting, PP3 supporting
Baylor Genetics	RCV003475999	SCV004211100	pathogenic	Leber congenital amaurosis 8	2023-10-26	criteria provided, single submitter	clinical testing