ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.715T>G (p.Tyr239Asp)
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.715T>G (p.Tyr239Asp)
Variation ID: 98889 Accession: VCV000098889.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68439571 (GRCh38) [ NCBI UCSC ] 1: 68905254 (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 Feb 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.715T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Tyr239Asp missense NC_000001.11:g.68439571A>C NC_000001.10:g.68905254A>C NG_008472.2:g.15389T>G Q16518:p.Tyr239Asp - Protein change
- Y239D
- Other names
- NM_000329.3(RPE65):c.715T>G
- Canonical SPDI
- NC_000001.11:68439570:A:C
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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) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
- | 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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (2) |
criteria provided, single submitter
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Apr 22, 2021 | RCV000085220.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 13, 2023 | RCV000678618.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2024 | RCV001207227.7 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2021 | RCV001831895.1 | |
Pathogenic (1) |
reviewed by expert panel
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Feb 18, 2024 | RCV003764797.1 |
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 18, 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: SCV004697378.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.715T>G is a predicted missense variant substituting tyrosine by aspartic acid at position 239. The computational predictor REVEL gives a score of 0.987, which is … (more)
NM_000329.3(RPE65):c.715T>G is a predicted missense variant substituting tyrosine by aspartic acid at position 239. The computational predictor REVEL gives a score of 0.987, which is above the ClinGen LCA / eoRD VCEP threshold of >= 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI also gives a score of 0.34 for splice acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 3/129118 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 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 32032261). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans (1 point, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt) and significant, documented improvement of blue full-field stimulus testing after treatment with RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (8.5 points, PMID: 21911650, PP4_Moderate). The variant exhibited between 1% (PMID: 24849605) and 5% (PMID: 19431183) enzymatic activity in retinoid isomerase assays 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 (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
(Apr 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001764548.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Observed in other patients with RPE65-related disorders in published literature (Galvin et al., 2005; Jacobson et al., 2009; Pasadhika et al., 2010); Published functional studies … (more)
Observed in other patients with RPE65-related disorders in published literature (Galvin et al., 2005; Jacobson et al., 2009; Pasadhika et al., 2010); Published functional studies demonstrate a damaging effect on protein function and expression (Philp et al., 2009; Redmond et al., 2010; Jin et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19959640, 22334370, 19117922, 24849605, 19920137, 26427455, 19431183, 16205573) (less)
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Pathogenic
(Oct 13, 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: SCV004209219.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 07, 2024)
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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: SCV001378571.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 239 of the RPE65 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 239 of the RPE65 protein (p.Tyr239Asp). This variant is present in population databases (rs61752896, gnomAD 0.002%). This missense change has been observed in individual(s) with retinitis pigmentosa or Leber congenital amaurosis (PMID: 20801516, 22334370, 26626312). 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: 98889). 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: 19431183, 24849605, 26427455). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis 2
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804706.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2021)
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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: SCV002092762.1
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: SCV000117357.1
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.715T>G
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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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Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark. | Astuti GD | European journal of human genetics : EJHG | 2016 | PMID: 26626312 |
Functional Rescue of Retinal Degeneration-Associated Mutant RPE65 Proteins. | Jin M | Advances in experimental medicine and biology | 2016 | PMID: 26427455 |
Rescue of enzymatic function for disease-associated RPE65 proteins containing various missense mutations in non-active sites. | Li S | The Journal of biological chemistry | 2014 | PMID: 24849605 |
Next-generation genetic testing for retinitis pigmentosa. | Neveling K | Human mutation | 2012 | PMID: 22334370 |
Simultaneous mutation detection in 90 retinal disease genes in multiple patients using a custom-designed 300-kb retinal resequencing chip. | Booij JC | Ophthalmology | 2011 | PMID: 20801516 |
Predicting the pathogenicity of RPE65 mutations. | Philp AR | Human mutation | 2009 | PMID: 19431183 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/862029ef-cc5c-4b10-b102-f9a252e48910 | - | - | - | - |
Text-mined citations for rs61752896 ...
HelpRecord last updated Mar 11, 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.