ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1418T>A (p.Val473Asp)
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.1418T>A (p.Val473Asp)
Variation ID: 98846 Accession: VCV000098846.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68431097 (GRCh38) [ NCBI UCSC ] 1: 68896780 (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 Feb 28, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.1418T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Val473Asp missense NC_000001.11:g.68431097A>T NC_000001.10:g.68896780A>T NG_008472.2:g.23863T>A Q16518:p.Val473Asp - Protein change
- V473D
- Other names
- NM_000329.3(RPE65):c.1418T>A
- Canonical SPDI
- NC_000001.11:68431096:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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.
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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not provided (1) |
no classification provided
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- | RCV000085173.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 20, 2020 | RCV001257424.1 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2023 | RCV001250706.4 | |
Likely pathogenic (1) |
reviewed by expert panel
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Jan 31, 2024 | RCV003764787.1 |
Submissions - Germline
Classification
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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
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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
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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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Likely Pathogenic
(Jan 31, 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: SCV004697419.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.1418T>A is a missense variant that substitutes valine with arginine at position 473. This variant has been reported in at least 2 unrelated probands with … (more)
NM_000329.3(RPE65):c.1418T>A is a missense variant that substitutes valine with arginine at position 473. This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 9501220, SCV001430890.1). This variant has also been reported in at least 1 probands with early-onset severe retinal dystrophy who was compound heterozygous with the p.Pro363Thr variant confirmed in trans (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one patient harboring the variant exhibits a phenotype including nondetectable ERG responses from rods (0.5 pts) and cones ( 1 pt), nyctalopia (0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), light staring (1 pt), and positive response to RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (13 total points, VCEP member-provided data, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.992, which is above the ClinGen LCA/eoRD VCEP PP3_Mod threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048441.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The observed variant c.1418T>A (p.Val473Asp) has previously been reported in homozygous state in a patient affected with leber congenital amaurosis and it lies in the … (more)
The observed variant c.1418T>A (p.Val473Asp) has previously been reported in homozygous state in a patient affected with leber congenital amaurosis and it lies in the retinal pigment epithelial membrane protein domain of the RPE65 protein (Morimura et al. 1998). The p.Val473Asp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely pathogenic. The amino acid Val at position 473 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val473Asp in RPE65 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Congenital blindness (present)
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Likely pathogenic
(Jan 21, 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: SCV004209287.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Aug 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Retinitis pigmentosa 20 (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001430890.1
First in ClinVar: Oct 01, 2020 Last updated: Oct 01, 2020 |
Comment:
A homozygous missense variation in exon 13 of the RPE65 gene that results in the amino acid substitution of Aspartic acid for Valine at codon … (more)
A homozygous missense variation in exon 13 of the RPE65 gene that results in the amino acid substitution of Aspartic acid for Valine at codon 473 was detected. The observed variant c.1418T>A (p.Val473Asp) lies in the retinal pigment epithelial membrane protein domain of the RPE65 protein (Morimura et al. 1998) and has previously been reported in homozygous state in a patient affected with leber congenital amaurosis. The variant has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Jaundice (present) , Night blindness (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Muslim
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis 2
Affected status: yes
Allele origin:
inherited
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Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001425584.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Number of individuals with the variant: 1
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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: SCV000117310.1
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.1418T>A
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001430890.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. | Morimura H | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9501220 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d1b42d5c-6dd4-4376-b088-49da0241c349 | - | - | - | - |
Text-mined citations for rs62637007 ...
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.