ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1543C>T (p.Arg515Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000329.3(RPE65):c.1543C>T (p.Arg515Trp)
Variation ID: 13120 Accession: VCV000013120.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68429835 (GRCh38) [ NCBI UCSC ] 1: 68895518 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Mar 10, 2024 Feb 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.1543C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Arg515Trp missense NC_000001.11:g.68429835G>A NC_000001.10:g.68895518G>A NG_008472.2:g.25125C>T Q16518:p.Arg515Trp - Protein change
- R515W
- Other names
- NM_000329.3(RPE65):c.1543C>T
- Canonical SPDI
- NC_000001.11:68429834:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RPE65 | - | - |
GRCh38 GRCh37 |
937 | 963 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2004 | RCV000013999.26 | |
Pathogenic (2) |
criteria provided, single submitter
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Jul 30, 2023 | RCV000014000.27 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 24, 2021 | RCV000085176.7 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000132583.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV000816506.8 | |
Pathogenic (2) |
criteria provided, single submitter
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Jul 28, 2023 | RCV001826461.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2023 | RCV003887868.1 | |
Pathogenic (1) |
reviewed by expert panel
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Feb 20, 2024 | RCV003764565.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 20, 2024)
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reviewed by expert panel
Method: curation
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RPE65-related recessive retinopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen
Accession: SCV004697423.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.1543C>T is a missense variant predicted to replace arginine with tryptophan at position 515. This variant is present in gnomAD v.2.1.1 at a GrpMax allele … (more)
NM_000329.3(RPE65):c.1543C>T is a missense variant predicted to replace arginine with tryptophan at position 515. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000002980, with 2 alleles / 126782 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). 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: 25495949). This variant has also been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) (PMID: 34492281)), NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) (PMID: 32032261), NM_000329.3(RPE65):c.1067dup (p.Asn356fs) (PMID: 35129589), or NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) variant (PMID: 30025081) variants suspected in trans (2 pts), which were all previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) based on exome sequencing-based genotyping that did not provide an alternative explanation for visual impairment (2 pts), night blindness (0.5 pts) with onset during the first year of life (1 pt), attenuated retinal vessels (0.5 pts), macular atrophy (0.5 pts), bone spicule pigmentation (0.5 pts), non-recordable electroretinogram pattern in rod (0.5 pts) and cone (1 pt) responses, and decreased central visual acuity (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMID: 25495949, PP4_Moderate). The computational predictor REVEL gives a score of 0.935, which is above the ClinGen LCA / eoRD VCEP threshold of >=0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited less than 10% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 25752820, PS3_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: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
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Pathogenic
(Jul 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209251.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Retinitis pigmentosa 20
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000957019.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 515 of the RPE65 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 515 of the RPE65 protein (p.Arg515Trp). This variant is present in population databases (rs121917745, gnomAD 0.008%). This missense change has been observed in individual(s) with retinal disease (PMID: 15557452, 26906952, 29681726, 31273949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13120). 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: 25752820). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Dept Of Ophthalmology, Nagoya University
Accession: SCV004705311.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Pathogenic
(Jul 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004028605.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: RPE65 c.1543C>T (p.Arg515Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: RPE65 c.1543C>T (p.Arg515Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248882 control chromosomes (gnomAD). c.1543C>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis, retinitis pigmentosa or Usher syndrome (Oishi_2014, Katagiri_2016, Koyanagi_2021). These data indicate that the variant is very likely to be associated with disease. At least one functional paper reports this variant affects protein function (Li_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25495949, 33629268, 25752820, 25324289). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019885.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Retinitis pigmentosa
Affected status: not provided
Allele origin:
not provided
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Department of Ophthalmology and Visual Sciences Kyoto University
Accession: SCV000172526.1
First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Dec 01, 2004)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 20
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034246.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2016 |
Comment on evidence:
In a 55-year-old Japanese woman, the child of consanguineous parents, who had been diagnosed with retinitis pigmentosa (RP20; 613794) at the age of 40, Kondo … (more)
In a 55-year-old Japanese woman, the child of consanguineous parents, who had been diagnosed with retinitis pigmentosa (RP20; 613794) at the age of 40, Kondo et al. (2004) detected a homozygous 1543C-T transition in the RPE65 gene that resulted in an arg515-to-trp (R515W) amino acid substitution. She had observed the development of night blindness in early childhood and had been free from visual disability until 24 years of age. Arg515 is located in a conserved RPE65-specific region. Kondo et al. (2004) noted that this mutation had been found in compound heterozygosity in Leber congenital amaurosis (LCA2; 204100). (less)
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Pathogenic
(Dec 01, 2004)
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no assertion criteria provided
Method: literature only
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LEBER CONGENITAL AMAUROSIS 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034247.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2016 |
Comment on evidence:
In a 55-year-old Japanese woman, the child of consanguineous parents, who had been diagnosed with retinitis pigmentosa (RP20; 613794) at the age of 40, Kondo … (more)
In a 55-year-old Japanese woman, the child of consanguineous parents, who had been diagnosed with retinitis pigmentosa (RP20; 613794) at the age of 40, Kondo et al. (2004) detected a homozygous 1543C-T transition in the RPE65 gene that resulted in an arg515-to-trp (R515W) amino acid substitution. She had observed the development of night blindness in early childhood and had been free from visual disability until 24 years of age. Arg515 is located in a conserved RPE65-specific region. Kondo et al. (2004) noted that this mutation had been found in compound heterozygosity in Leber congenital amaurosis (LCA2; 204100). (less)
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Pathogenic
(Feb 10, 2020)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002092732.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000117313.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_RPE65:c.1543C>T
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Regional differences in genes and variants causing retinitis pigmentosa in Japan. | Koyanagi Y | Japanese journal of ophthalmology | 2021 | PMID: 33629268 |
RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye diseases in China. | Li S | Acta ophthalmologica | 2020 | PMID: 31273949 |
Early onset flecked retinal dystrophy associated with new compound heterozygous RPE65 variants. | Katagiri S | Molecular vision | 2018 | PMID: 29681726 |
Preserved visual function in retinal dystrophy due to hypomorphic RPE65 mutations. | Hull S | The British journal of ophthalmology | 2016 | PMID: 26906952 |
RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis. | Katagiri S | Ophthalmic genetics | 2016 | PMID: 25495949 |
Temperature-sensitive retinoid isomerase activity of RPE65 mutants associated with Leber Congenital Amaurosis. | Li S | Journal of biochemistry | 2015 | PMID: 25752820 |
Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. | Oishi M | Investigative ophthalmology & visual science | 2014 | PMID: 25324289 |
A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers. | Kondo H | Investigative ophthalmology & visual science | 2004 | PMID: 15557452 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/62e2905f-cba8-449d-85c5-7f56947cd41a | - | - | - | - |
Text-mined citations for rs121917745 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.