ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1292A>G (p.Tyr431Cys)
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.1292A>G (p.Tyr431Cys)
Variation ID: 29873 Accession: VCV000029873.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p31.3 1: 68431328 (GRCh38) [ NCBI UCSC ] 1: 68897011 (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.1292A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Tyr431Cys missense NC_000001.11:g.68431328T>C NC_000001.10:g.68897011T>C NG_008472.2:g.23632A>G Q16518:p.Tyr431Cys - Protein change
- Y431C
- Other names
- NM_000329.3(RPE65):c.1292A>G
- Canonical SPDI
- NC_000001.11:68431327:T:C
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | 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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, single submitter
|
Sep 29, 2023 | RCV000022754.19 | |
Likely pathogenic (2) |
criteria provided, single submitter
|
Nov 26, 2019 | RCV000085161.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 8, 2023 | RCV001054426.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 28, 2023 | RCV003317042.1 | |
Likely pathogenic (1) |
reviewed by expert panel
|
Jan 31, 2024 | RCV003764628.1 |
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: SCV004697375.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.1292A>G is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 431. This variant is present in gnomAD v.2.1.1 at … (more)
NM_000329.3(RPE65):c.1292A>G is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 431. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 1/113326 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 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.907A>T (p.Lys303Ter) or c.1102T>C (p.Tyr368His) variants confirmed in trans (2 point, PMIDs: 14962443, 30268864), which were 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 pts), absent or severely decreased rod electroretinogram responses (0.5 pts), congenital night blindness (0.5 pts), optic nerve pallor (0.5 pts), Pigmentary retinopathy with attenuated vessels (0.5 pts), macular atrophy (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), abnormal color vision or evidence of cone involvement on ERG (1 pt), nystagmus (1 pt), and significant improvement following gene therapy (8 pt) which together are highly specific for RPE65-related recessive retinopathy (PMIDs: 14962443, 19117922, 22323828, 15 points, PP4_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the ClinGen LCA / eoRD VCEP 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 likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRP VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
|
|
Likely pathogenic
(Jun 28, 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: SCV004020560.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: RPE65 c.1292A>G (p.Tyr431Cys) 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.1292A>G (p.Tyr431Cys) 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 4e-06 in 250892 control chromosomes (gnomAD). c.1292A>G has been reported in the literature in individuals affected with Leber Congenital Amaurosis or inherited retinal dystrophy (examples: Al-Khayer_2004, Chung_2019, Kumaran_2020). Multiple reports have classified this variant as likely pathogenic (Hanany_2020 and Johnston_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15837919, 14962443, 19117922, 30268864, 31964843, 17964524, 34906458, 32347917, 30025081). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
Likely pathogenic
(Sep 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209228.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Nov 08, 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: SCV001218739.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 431 of the RPE65 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 431 of the RPE65 protein (p.Tyr431Cys). This variant is present in population databases (rs62636300, gnomAD 0.0009%). This missense change has been observed in individual(s) with Leber congenital amaurosis or clinical features of inherited retinal dystrophy (PMID: 14962443, 19117922, 30268864; 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: 29873). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Nov 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001790937.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30268864, 14962443) (less)
|
|
Pathogenic
(Feb 01, 2004)
|
no assertion criteria provided
Method: literature only
|
LEBER CONGENITAL AMAUROSIS 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044043.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2016 |
Comment on evidence:
For discussion of the tyr431-to-cys (Y431C) mutation that was found in compound heterozygous state in a woman with Leber congenital amaurosis (LCA2; 204100) by Al-Khayer … (more)
For discussion of the tyr431-to-cys (Y431C) mutation that was found in compound heterozygous state in a woman with Leber congenital amaurosis (LCA2; 204100) by Al-Khayer et al. (2004), see 180069.0011. (less)
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117298.1
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.1292A>G
|
|
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 |
---|---|---|---|---|
The ACMG SF v3.0 gene list increases returnable variant detection by 22% when compared with v2.0 in the ClinSeq cohort. | Johnston JJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906458 |
Retinal Structure in RPE65-Associated Retinal Dystrophy. | Kumaran N | Investigative ophthalmology & visual science | 2020 | PMID: 32347917 |
Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. | Hanany M | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31964843 |
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 |
Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. | Jacobson SG | Investigative ophthalmology & visual science | 2009 | PMID: 19117922 |
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. | Stone EM | American journal of ophthalmology | 2007 | PMID: 17964524 |
Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. | Jacobson SG | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 15837919 |
Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations. | Al-Khayer K | American journal of ophthalmology | 2004 | PMID: 14962443 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/73c10d63-6456-4cf2-bf6b-506b7e13cfde | - | - | - | - |
Text-mined citations for rs62636300 ...
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.