rs62642583
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000329.3(RPE65):c.292_311del(p.Ile98HisfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I98I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000329.3 frameshift
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.292_311del | p.Ile98HisfsTer26 | frameshift_variant | 4/14 | ENST00000262340.6 | |
LOC124904198 | XR_007066164.1 | n.72-3712_72-3693del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPE65 | ENST00000262340.6 | c.292_311del | p.Ile98HisfsTer26 | frameshift_variant | 4/14 | 1 | NM_000329.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251352Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135840
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461864Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727232
GnomAD4 genome AF: 0.000131 AC: 20AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74356
ClinVar
Submissions by phenotype
Leber congenital amaurosis 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11462243). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000098860 / PMID: 10766140 , 32347917 , 35129589). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 10, 2023 | - - |
Leber congenital amaurosis Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | research | Cytogenetics and Genomics Laboratory, Medical University of South Carolina | Jun 01, 2018 | - - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2020 | Frameshift 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, 31589614, 30870047, 10766140, 28181551) - |
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_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) is a deletion variant in exon 4 of 14 that causes a frameshift and introduces a premature stop after 26 codons. This frameshift is predicted to trigger nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). A number of affected patients have been reported harboring this variant, including at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30870047, PM3). This variant has a Grpmax filtering allele frequency of 0.0001565 (10/34580) in the Latino / Admixed American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<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, PM3, and PM2_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 | Jun 25, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 98860). This premature translational stop signal has been observed in individuals with RPE65-related conditions (PMID: 10766140, 28181551). This variant is present in population databases (rs767212885, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Ile98Hisfs*26) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at