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

gnomAD frequency: 0.00006  dbSNP: rs61752871

Total submissions: 16

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	2024-03-27	criteria provided, single submitter	clinical testing
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