rs61752871
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000329.3(RPE65):c.271C>T(p.Arg91Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R91Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000329.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPE65 | NM_000329.3 | c.271C>T | p.Arg91Trp | missense_variant | 4/14 | ENST00000262340.6 | |
LOC124904198 | XR_007066164.1 | n.72-3674G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPE65 | ENST00000262340.6 | c.271C>T | p.Arg91Trp | missense_variant | 4/14 | 1 | NM_000329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251212Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
GnomAD4 exome AF: 0.0000732 AC: 107AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 727222
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74418
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | RPE65: PM3:Very Strong, PM2, PM5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 13, 2023 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2022 | 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) - |
Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 26, 2017 | - - |
Leber congenital amaurosis 2 Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 23, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Retinitis pigmentosa 20 Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 17, 1998 | - - |
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Faculty of Health Sciences, Beirut Arab University | Nov 22, 2016 | - - |
Abnormality of the eye Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Leber congenital amaurosis;C3151086:Retinitis pigmentosa 20;CN239301:RPE65-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | 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). - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 15, 2019 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at