ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.370C>T (p.Arg124Ter)
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.370C>T (p.Arg124Ter)
Variation ID: 98866 Accession: VCV000098866.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68444656 (GRCh38) [ NCBI UCSC ] 1: 68910339 (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.370C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Arg124Ter nonsense NC_000001.11:g.68444656G>A NC_000001.10:g.68910339G>A NG_008472.2:g.10304C>T - Protein change
- R124*
- Other names
- NM_000329.3(RPE65):c.370C>T
- p.Arg124Ter
- Canonical SPDI
- NC_000001.11:68444655: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00013
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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
Help
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 (2) |
criteria provided, single submitter
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Aug 20, 2019 | RCV000085195.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2024 | RCV000538669.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000986332.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 19, 2023 | RCV001275332.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV002490740.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 12, 2023 | RCV003242981.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2023 | RCV003888467.1 | |
Pathogenic (1) |
reviewed by expert panel
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Feb 20, 2024 | RCV003764794.1 |
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: SCV004697429.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a nonsense variant that introduces a premature stop codon into exon 5 of 14, and is predicted to lead to nonsense-mediated decay … (more)
NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a nonsense variant that introduces a premature stop codon into exon 5 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002191, with 9 alleles / 24480 total alleles in the African/African-American 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: 35129589, PM3_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: PVS1, PM2_Supporting, PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
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Pathogenic
(May 28, 2019)
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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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Mendelics
Accession: SCV001135305.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Aug 20, 2019)
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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: SCV001795678.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32865313, 33576794, 30996589, 31630094, 31736247, 30608580, 28559085, 30268864, 29332120, 9501220, 19854499, 11095629, 25257057, 20683928, 28005406, 15691574, 28945494, 28237426, 20079931, 25525159) (less)
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Pathogenic
(Jan 19, 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: SCV003800725.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: RPE65 c.370C>T (p.Arg124X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: RPE65 c.370C>T (p.Arg124X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in HGMD in association with Leber congenital amaurosis and Retinal degeneration. The variant allele was found at a frequency of 3.6e-05 in 250738 control chromosomes. c.370C>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis and inherited retinal dystrophies (examples: Galvin_2005, Zhong_2019, Zenteno_2019, Lopez-Rodriguez_2021, Testa_2022). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003942962.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The c.370C>T (p.R124*) alteration, located in coding exon 5 of the RPE65 gene, consists of a C to T substitution at nucleotide position 370. This … (more)
The c.370C>T (p.R124*) alteration, located in coding exon 5 of the RPE65 gene, consists of a C to T substitution at nucleotide position 370. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 124. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (16/282008) total alleles studied. The highest observed frequency was 0.037% (9/24480) of African alleles. This variant has been reported in compound heterozygous state in multiple individuals with RPE65-related retinopathies (Kumaran, 2018; Chung, 2019; Maltese, 2022). This variant has also been reported as a homozygous finding in an child with Leber congenital amaurosis whose parents were consanguineous (Zhong, 2019). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Oct 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: SCV004209207.1
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: SCV000644182.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg124*) in the RPE65 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg124*) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs61752877, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 9501220, 19854499, 20683928). ClinVar contains an entry for this variant (Variation ID: 98866). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: SCV004705508.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Pathogenic
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Retinitis pigmentosa 20 Retinitis pigmentosa 87 with choroidal involvement
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002797742.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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: SCV001425582.1
First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Sep 16, 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: SCV001460406.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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: SCV000117332.1
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.370C>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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Genetics of Inherited Retinal Diseases in Understudied Ethnic Groups in Italian Hospitals. | Maltese PE | Frontiers in genetics | 2022 | PMID: 35836572 |
RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study. | Testa F | Investigative ophthalmology & visual science | 2022 | PMID: 35129589 |
RPE65-related retinal dystrophy: Mutational and phenotypic spectrum in 45 affected patients. | Lopez-Rodriguez R | Experimental eye research | 2021 | PMID: 34492281 |
Extensive genic and allelic heterogeneity underlying inherited retinal dystrophies in Mexican patients molecularly analyzed by next-generation sequencing. | Zenteno JC | Molecular genetics & genomic medicine | 2020 | PMID: 31736247 |
Seven novel variants expand the spectrum of RPE65-related Leber congenital amaurosis in the Chinese population. | Zhong Z | Molecular vision | 2019 | PMID: 30996589 |
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 |
Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. | Coppieters F | Human mutation | 2010 | PMID: 20683928 |
Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. | Maguire AM | Lancet (London, England) | 2009 | PMID: 19854499 |
Leber congenital amaurosis: genes, proteins and disease mechanisms. | den Hollander AI | Progress in retinal and eye research | 2008 | PMID: 18632300 |
Evaluation of genotype-phenotype associations in leber congenital amaurosis. | Galvin JA | Retina (Philadelphia, Pa.) | 2005 | PMID: 16205573 |
Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. | Zernant J | Investigative ophthalmology & visual science | 2005 | PMID: 16123401 |
Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. | Redmond TM | Nature genetics | 1998 | PMID: 9843205 |
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 |
Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. | Gu SM | Nature genetics | 1997 | PMID: 9326941 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/86306b55-3d7f-4eb7-885d-46f107384d83 | - | - | - | - |
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Text-mined citations for rs61752877 ...
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.