rs368088025
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000329.3(RPE65):c.130C>T(p.Arg44Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,810 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
Consequence
NM_000329.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPE65 | NM_000329.3 | c.130C>T | p.Arg44Ter | stop_gained | 3/14 | ENST00000262340.6 | |
LOC124904198 | XR_007066164.1 | n.72-1707G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPE65 | ENST00000262340.6 | c.130C>T | p.Arg44Ter | stop_gained | 3/14 | 1 | NM_000329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251478Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461616Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727104
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
RPE65-related recessive retinopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jan 19, 2022 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen | Feb 20, 2024 | NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) is a nonsense variant that introduces a premature stop codon into exon 3 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 one proband with early-onset severe retinal dystrophy and harboring this variant exhibits a phenotype including onset by age 1 (1 pt), ERG with extinguished responses from rods (0.5 pts) and cones (1 pts), nystagmus ( 1pt), and attenuated retinal blood vessels (0.5 pts), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 26626312, PP4). The variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00001685, with 7 alleles/129188 total alleles in the European non-Finnish 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, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31630094, 30996589, 30268864, 29178642, 15765048, 26626312, 24129572, 32067411) - |
Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg44*) 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 (rs368088025, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 26626312). ClinVar contains an entry for this variant (Variation ID: 374497). For these reasons, this variant has been classified as Pathogenic. - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Leber congenital amaurosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 08, 2023 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
RPE65-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 02-05-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at