ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs61752871
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085184 SCV000329499 pathogenic not provided 2022-07-19 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with decreased enzyme activity, decreased protein expression, and accelerated degradation compared to wild type (Takahashi et al., 2006; Li et al., 2015); This variant is associated with the following publications: (PMID: 16205573, 16518657, 19117922, 17197551, 18936139, 9501220, 18682808, 18539930, 18722466, 11095629, 16505056, 18809924, 30268864, 19431183, 25257057, 25752820, 19854499, 17525851, 24997176, 21911650, 18774912, 10937591, 10766140, 17964524, 17933883, 21304899, 27874104, 26427430, 31054281, 31925606, 22334370, 16754667, 31273949)
Invitae RCV000527143 SCV000644184 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2023-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 91 of the RPE65 protein (p.Arg91Trp). This variant is present in population databases (rs61752871, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive RPE65-related conditions (PMID: 9501220, 10766140, 10937591, 11095629, 18682808, 26626312; 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: 13115). 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 RPE65 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16754667, 25752820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000527143 SCV000794489 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-09-26 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073556 SCV001239105 pathogenic Retinal dystrophy 2019-06-15 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV001095690 SCV001251494 pathogenic Retinitis pigmentosa 20; Leber congenital amaurosis; RPE65-related disorder criteria provided, single submitter research The RPE65 c.271C>T (p.R91W) variant has been reported in the homozygous or compound heterozygous state in individuals with Leber congenital amaurosis, retinitis pigmentosa, or inherited retinal degeneration (PMID: 9501220; 10937591; 11095629; 18682808; 19117922; 21153841).
Baylor Genetics RCV001250682 SCV001520554 pathogenic Leber congenital amaurosis 2 2019-08-23 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000013994 SCV001573631 pathogenic Retinitis pigmentosa 20 2021-04-08 criteria provided, single submitter research The RPE65 c.271C>T 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: PS3, PP1-S, PM2. Based on this evidence we have classified this variant as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001813981 SCV001755470 pathogenic Abnormality of the eye 2021-07-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000085184 SCV003824931 pathogenic not provided 2023-01-13 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085184 SCV004009855 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing RPE65: PM3:Very Strong, PM2, PM5, PP3
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
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787698 SCV000926690 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001250682 SCV001425552 likely pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Faculty of Health Sciences, Beirut Arab University RCV001257818 SCV001434602 pathogenic Autosomal recessive retinitis pigmentosa 2016-11-22 no assertion criteria provided literature only
Natera, Inc. RCV001275337 SCV001460411 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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