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

gnomAD frequency: 0.00006  dbSNP: rs61752871

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	RCV004595852	SCV005088580	pathogenic	RPE65-related recessive retinopathy	2024-07-23	reviewed by expert panel	curation	NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) is a missense variant predicted to replace arginine with tryptophan at position 91. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.0001329, with 16 alleles / 74990 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 4 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 35129589, 18722466). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.11+5G>A or NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variants suspected in trans (1 point, PMIDs: 35129589, 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant was genotyped by next-generation sequencing analysis of 586 candidate genes which did not provide an alternative explanation for visual impairment (2 pts) and exhibits a phenotype including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), mild myopia, extinguished scotopic (0.5 pts) and photopic (1 pt) ERG responses, bone spicule pigmentation of the fundus (0.5 pts), white or yellow dots in fundus (2 pts), and nystagmus (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 total points, PMID: 31925606, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PMID: 31925606, PP1_Moderate). The computational predictor REVEL gives a score of 0.852, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.22, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and predicts a damaging impact on splicing. Another missense variant in the same codon, NM_000329.3(RPE65):c.272G>A (p.Arg91Gln), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5). Splicing predictions using SpliceAI are equivalent for both of these variants. The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 16754667, PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_strong, PP4_moderate, PP1_moderate, PP3_moderate, PM5, and PS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527143	SCV000644184	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-11-18	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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073556	SCV005071032	pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001275337	SCV005381604	pathogenic	Leber congenital amaurosis	2024-08-02	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.271C>T (p.Arg91Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251212 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RPE65 causing Leber Congenital Amaurosis (5.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.271C>T has been reported in the literature in multiple individuals affected with early-onset retinal degeneration (example: Matri_2006). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 16518657). ClinVar contains an entry for this variant (Variation ID: 13115). Based on the evidence outlined above, the variant was classified as pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000013994	SCV005420654	pathogenic	Retinitis pigmentosa 20	2024-10-04	criteria provided, single submitter	research	PS3,PM3(strong),PM2,PP3,PP1,PM5
Fulgent Genetics, Fulgent Genetics	RCV005031436	SCV005664063	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2024-03-12	criteria provided, single submitter	clinical testing
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