rs61752877
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2_SupportingPM3_Supporting
This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a nonsense variant that introduces a premature stop codon into exon 5 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). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002191, with 9 alleles / 24480 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 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID:35129589, PM3_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, PM2_Supporting, PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226545/MONDO:0100368/120
Frequency
Consequence
NM_000329.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPE65 | NM_000329.3 | c.370C>T | p.Arg124Ter | stop_gained | 5/14 | ENST00000262340.6 | |
LOC124904198 | XR_007066164.1 | n.72-3876G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPE65 | ENST00000262340.6 | c.370C>T | p.Arg124Ter | stop_gained | 5/14 | 1 | NM_000329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 151960Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250738Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135800
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727218
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74324
ClinVar
Submissions by phenotype
Leber congenital amaurosis 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Leber congenital amaurosis Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2023 | Variant summary: RPE65 c.370C>T (p.Arg124X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in HGMD in association with Leber congenital amaurosis and Retinal degeneration. The variant allele was found at a frequency of 3.6e-05 in 250738 control chromosomes. c.370C>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis and inherited retinal dystrophies (examples: Galvin_2005, Zhong_2019, Zenteno_2019, Lopez-Rodriguez_2021, Testa_2022). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2019 | 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: 32865313, 33576794, 30996589, 31630094, 31736247, 30608580, 28559085, 30268864, 29332120, 9501220, 19854499, 11095629, 25257057, 20683928, 28005406, 15691574, 28945494, 28237426, 20079931, 25525159) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2023 | The c.370C>T (p.R124*) alteration, located in coding exon 5 of the RPE65 gene, consists of a C to T substitution at nucleotide position 370. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 124. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (16/282008) total alleles studied. The highest observed frequency was 0.037% (9/24480) of African alleles. This variant has been reported in compound heterozygous state in multiple individuals with RPE65-related retinopathies (Kumaran, 2018; Chung, 2019; Maltese, 2022). This variant has also been reported as a homozygous finding in an child with Leber congenital amaurosis whose parents were consanguineous (Zhong, 2019). Based on the available evidence, this alteration is classified as pathogenic. - |
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 | Feb 20, 2024 | NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a nonsense variant that introduces a premature stop codon into exon 5 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). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002191, with 9 alleles / 24480 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 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PM3_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, PM2_Supporting, PM3_Supporting. (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 | Jan 07, 2024 | This sequence change creates a premature translational stop signal (p.Arg124*) 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 (rs61752877, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 9501220, 19854499, 20683928). ClinVar contains an entry for this variant (Variation ID: 98866). 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 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2022 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at