ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1451G>A (p.Gly484Asp)
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
-
NM_000329.3(RPE65):c.1451G>A (p.Gly484Asp)
Variation ID: 98848 Accession: VCV000098848.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p31.3 1: 68429927 (GRCh38) [ NCBI UCSC ] 1: 68895610 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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
-
Nucleotide Protein Molecular
consequenceNM_000329.3:c.1451G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Gly484Asp missense NC_000001.11:g.68429927C>T NC_000001.10:g.68895610C>T NG_008472.2:g.25033G>A - Protein change
- G484D
- Other names
- NM_000329.3(RPE65):c.1451G>A
- p.Gly484Asp
- Canonical SPDI
- NC_000001.11:68429926:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
RPE65 | - | - |
GRCh38 GRCh37 |
937 | 965 |
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. |
---|---|---|---|---|
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 3, 2020 | RCV000085175.5 | |
Likely pathogenic (2) |
criteria provided, single submitter
|
Jul 3, 2023 | RCV001250703.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 12, 2023 | RCV001826773.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 17, 2023 | RCV001854497.3 | |
Likely pathogenic (1) |
reviewed by expert panel
|
Jan 31, 2024 | RCV003764788.1 |
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
Help
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. |
|
---|---|---|---|---|---|
Likely Pathogenic
(Jan 31, 2024)
|
reviewed by expert panel
Method: curation
|
RPE65-related recessive retinopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen
Accession: SCV004697408.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.1451G>A is a predicted missense variant substituting glycine by aspartic acid at position 484. The computational predictor REVEL gives a score of 0.984, which is … (more)
NM_000329.3(RPE65):c.1451G>A is a predicted missense variant substituting glycine by aspartic acid at position 484. The computational predictor REVEL gives a score of 0.984, which is above the ClinGen LCA / eoRD VCEP threshold of >=0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Additionally, the splicing impact predictor SpliceAI gives a score of 0.23, 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 0.00005447, with 1/18360 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002. This variant has been reported in least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30025081, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts), absent or severely decreased rod electroretinogram response (0.5 pts), abnormal cone ERG responses (1 pt), white dots on color photography in the context of severe retinal dysfunction (2 pts), poor pupillary light response (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), decreased central visual acuity (1 pt), RPE mottling (0.5 pts), macular atrophy (0.5 pts), and symptomatic onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total points, PMID: 20811047, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
|
|
Likely pathogenic
(Aug 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565496.4
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
Comment:
The G484D variant has been reported previously in association with autosomal recessive retinitis pigmentosa (Stone et al., 2003) and in another individual with Severe Early … (more)
The G484D variant has been reported previously in association with autosomal recessive retinitis pigmentosa (Stone et al., 2003) and in another individual with Severe Early Childhood Onset Retinal Dystrophy (SECORD) presenting with a remarkable preservation of vision with adequate lighting and white retinal dots that were seen to fade with time and were replaced by RPE changes (Weleber et al., 2011). The G484D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G484D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. One other variant in a nearby residue (D477G) has been reported in the Human Gene Mutation Database in association with and RPE65-related disorder (Stenson et al., 2014). Therefore, based on the currently available information, G484D is a likely pathogenic variant. (less)
|
|
Likely pathogenic
(Jan 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800728.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: RPE65 c.1451G>A (p.Gly484Asp) 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.1451G>A (p.Gly484Asp) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 248526 control chromosomes (gnomAD). c.1451G>A has been reported in the literature in individuals affected with RPE65-related conditions (examples: Weleber_2011, Biswas_2017, Kumaran_2018, Chung_2019, Patel_2019, Lopez-Rodriguez_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
Pathogenic
(Jul 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004012155.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Clinical Features:
Hyperopic astigmatism (present) , Strabismus (present) , Pigmentary retinopathy (present) , Upbeat nystagmus (present)
|
|
Likely pathogenic
(Jul 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209260.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely pathogenic
(Nov 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019069.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Nov 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV002266185.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 484 of the RPE65 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 484 of the RPE65 protein (p.Gly484Asp). This variant is present in population databases (rs62653015, gnomAD 0.006%). This missense change has been observed in individual(s) with RPE65-related conditions (PMID: 20811047, 29332120, 30653986; Invitae). 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: 98848). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly484 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been observed in individuals with RPE65-related conditions (PMID: 33308271), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Leber congenital amaurosis 2
Affected status: yes
Allele origin:
inherited
|
Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001425578.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Number of individuals with the variant: 2
|
|
Likely pathogenic
(Sep 24, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002092736.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117312.1
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.1451G>A
|
|
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 |
---|---|---|---|---|
RPE65-related retinal dystrophy: Mutational and phenotypic spectrum in 45 affected patients. | Lopez-Rodriguez R | Experimental eye research | 2021 | PMID: 34492281 |
Novel gene variants in Polish patients with Leber congenital amaurosis (LCA). | Skorczyk-Werner A | Orphanet journal of rare diseases | 2020 | PMID: 33308271 |
Cone Spacing Correlates With Retinal Thickness and Microperimetry in Patients With Inherited Retinal Degenerations. | Foote KG | Investigative ophthalmology & visual science | 2019 | PMID: 30924848 |
The Oculome Panel Test: Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders. | Patel A | Ophthalmology | 2019 | PMID: 30653986 |
The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. | Chung DC | American journal of ophthalmology | 2019 | PMID: 30268864 |
A Cross-Sectional and Longitudinal Study of Retinal Sensitivity in RPE65-Associated Leber Congenital Amaurosis. | Kumaran N | Investigative ophthalmology & visual science | 2018 | PMID: 30025081 |
Severe Loss of Tritan Color Discrimination in RPE65 Associated Leber Congenital Amaurosis. | Kumaran N | Investigative ophthalmology & visual science | 2018 | PMID: 29332120 |
Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association. | Biswas P | Physiological genomics | 2017 | PMID: 28130426 |
The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis. | Weleber RG | Investigative ophthalmology & visual science | 2011 | PMID: 20811047 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b019b4c2-083e-4ca6-9a88-f11f9ca858c7 | - | - | - | - |
Text-mined citations for rs62653015 ...
HelpRecord last updated Mar 17, 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.