ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) (rs61752871)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000527143 SCV000794489 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000085184 SCV000329499 pathogenic not provided 2016-07-26 criteria provided, single submitter clinical testing The R91W variant in the RPE65 gene has been reported previously in the homozygous state and in the presence of a second RPE65 variant in individuals with Leber's congenital amaurosis, retinitis pigmentosa and early onset retinal degeneration (Morimura et al., 1998; El Matri et al., 2006; Seong et al., 2008; Li et al., 2009; Jacobson et al., 2009; Neveling et al., 2012). The R91W variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R91W 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 and this substitution occurs at a position that is conserved across species. Functional studies with TQBI-293A cells transfected with wild type and the R91W variant showed decreased protein, but not mRNA, levels in R91W cells and R91W displayed significantly accelerated degradation compared to wild type. In vitro assays showed decreased enzymatic activity in the R91W variant cells (Takahashi et al., 2006). Different missense variants at the same residue (R91Q; R91P) and in the nearby residue (E95Q) have been reported in the Human Gene Mutation Database in association with RPE65-related disorders, supporting the functional importance of this region of the protein. Therefore, we interpret R91W as a pathogenic variant.
Invitae RCV000527143 SCV000644184 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-04-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 91 of the RPE65 protein (p.Arg91Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs61752871, ExAC 0.07%). This variant has been reported in many individuals affected with Leber congenital amaurosis, retinitis pigmentosa or early-onset retinal degeneration, and is considered one of the most common pathogenic variants in the RPE65 gene (PMID: 10766140, 11095629, 18682808, 26626312). It has also been reported to segregate with disease in several families (PMID: 9501220, 10937591). ClinVar contains an entry for this variant (Variation ID: 13115). Experimental studies have shown that this missense change results in normal mRNA expression, but rapid protein degradation in cell culture (PMID: 16754667, 25752820). For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787698 SCV000926690 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
OMIM RCV000013994 SCV000034241 pathogenic Retinitis pigmentosa 20 1998-03-17 no assertion criteria provided literature only
Retina International RCV000085184 SCV000117321 not provided not provided no assertion provided not provided

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