rs61752895
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000329.3(RPE65):c.700C>T(p.Arg234Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000136 in 1,613,710 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
RPE65
NM_000329.3 stop_gained
NM_000329.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.36
Genes affected
RPE65 (HGNC:10294): (retinoid isomerohydrolase RPE65) The protein encoded by this gene is a component of the vitamin A visual cycle of the retina which supplies the 11-cis retinal chromophore of the photoreceptors opsin visual pigments. It is a member of the carotenoid cleavage oxygenase superfamily. All members of this superfamily are non-heme iron oxygenases with a seven-bladed propeller fold and oxidatively cleave carotenoid carbon:carbon double bonds. However, the protein encoded by this gene has acquired a divergent function that involves the concerted O-alkyl ester cleavage of its all-trans retinyl ester substrate and all-trans to 11-cis double bond isomerization of the retinyl moiety. As such, it performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Mutations in this gene are associated with early-onset severe blinding disorders such as Leber congenital. [provided by RefSeq, Oct 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-68439586-G-A is Pathogenic according to our data. Variant chr1-68439586-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-68439586-G-A is described in Lovd as [Pathogenic]. Variant chr1-68439586-G-A is described in Lovd as [Pathogenic]. Variant chr1-68439586-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPE65 | NM_000329.3 | c.700C>T | p.Arg234Ter | stop_gained | 7/14 | ENST00000262340.6 | |
LOC124904198 | XR_007066164.1 | n.72-8946G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPE65 | ENST00000262340.6 | c.700C>T | p.Arg234Ter | stop_gained | 7/14 | 1 | NM_000329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251384Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135860
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461614Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727122
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Leber congenital amaurosis 2 Pathogenic:3
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 05, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1997 | - - |
RPE65-related recessive retinopathy Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen | Dec 22, 2023 | NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) is a nonsense variant that introduces a premature stop codon in exon 7 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 6 probands have been reported with this variant, one of whom displayed nystagmus (1 pt), night blindness (0.5 pts), reduced visual acuity (1 pt), narrowing of retinal vessels (0.5 pts), moderate pallor of the optic discs (0.5 pts), difficulty discriminating any color (1 pt), unrecordable ERG (0.5 pts), absent autofluorescence (2 pts), and onset at birth (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMIDs: 9326927, PMID: 11264131 PMID: 15288992, PP4_moderate). Additionally, the variant has been reported to segregate with the phenotype (confirmed by absent ERG) in the proband plus one similarly affected sibling harboring the variant in the compound heterozygous state (PP1; PMID: 9326927). PM3 was not considered to avoid circularity, despite the presence of compound heterozygous cases harboring this variant as well as the p.Asn356fs, c.991_993dup (p.Trp331dup), or p.Arg124Ter variant. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002299, with 3 alleles / 34580 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_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: PVS1, PP4_Moderate, PM2_Supporting, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023) - |
Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Arg234*) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs61752895, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophy (PMID: 9326927, 30268864). 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: 13114). 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. - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 20, 2020 | - - |
Retinitis pigmentosa 20 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The RPE65 c.700C>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: PP1-M, PM2, PVS1. Based on this evidence we have classified this variant as Pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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