ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)
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.1022T>C (p.Leu341Ser)
Variation ID: 13118 Accession: VCV000013118.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68438293 (GRCh38) [ NCBI UCSC ] 1: 68903976 (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 Apr 4, 2013 Feb 28, 2024 Feb 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.1022T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Leu341Ser missense NC_000001.11:g.68438293A>G NC_000001.10:g.68903976A>G NG_008472.2:g.16667T>C Q16518:p.Leu341Ser - Protein change
- L341S
- Other names
- NP_000320.1:p.(Leu341Ser)
- NM_000329.3(RPE65):c.1022T>C
- Canonical SPDI
- NC_000001.11:68438292:A:G
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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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 | ||
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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
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
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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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Pathogenic (2) |
criteria provided, single submitter
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Jun 5, 2023 | RCV000013997.25 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 19, 2021 | RCV000085141.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2023 | RCV000986328.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV001047062.5 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 24, 2023 | RCV001831568.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 12, 2021 | RCV002496352.1 | |
Pathogenic (1) |
reviewed by expert panel
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Feb 20, 2024 | RCV003764564.1 |
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. |
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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: SCV004697398.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed … (more)
The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID: 23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID: 9501220) and two probands were homozygous for the variant (PMID: 9501220, PMID: 15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID: 9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (PM2_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: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_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: SCV001135301.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Mar 19, 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: SCV001779274.1
First in ClinVar: Aug 12, 2021 Last updated: Aug 12, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32865313, 32036094, 19854499, 21862650, 19753312, 30268864, 9501220, 29186038, 20079931, 20683928, 20811047, 27375040, 19117922, 18539930, 21153841, 10800710, 17964524) (less)
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Pathogenic
(Oct 26, 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: SCV004209209.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521281.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013118). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20079931) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:9501220). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Retinal dystrophy (present)
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Pathogenic
(Aug 12, 2021)
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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: SCV002805138.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 20
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003929442.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Clinical Features:
Congenital stationary night blindness (present) , Pigmentary retinal dystrophy (present)
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Likely pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: research
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Leber congenital amaurosis
Affected status: yes
Allele origin:
germline
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Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030303.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 4
Sex: mixed
Geographic origin: Portugal
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Pathogenic
(Jan 28, 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: SCV001210996.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 341 of the RPE65 protein (p.Leu341Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 341 of the RPE65 protein (p.Leu341Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 9501220, 18539930, 19854499, 20079931, 20683928). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13118). 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 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 1998)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 20
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034244.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 patients with autosomal recessive retinitis pigmentosa (RP20; 613794), Morimura et al. (1998) identified mutations in the RPE65 gene that are likely to be … (more)
In 3 patients with autosomal recessive retinitis pigmentosa (RP20; 613794), Morimura et al. (1998) identified mutations in the RPE65 gene that are likely to be pathogenic. In 1 of the families, 1 individual with RP was homozygous for a leu341-to-ser mutation, whereas 4 other individuals with RP in other branches of the family were compound heterozygotes for this mutation and a 4-bp insertion affecting glu404. (less)
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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: SCV001425565.1
First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 18, 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: SCV002092750.1
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: SCV000117278.1
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.1022T>C
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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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The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. | Peter VG | PNAS nexus | 2023 | PMID: 36909829 |
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 |
Visual acuity in patients with Leber's congenital amaurosis and early childhood-onset retinitis pigmentosa. | Walia S | Ophthalmology | 2010 | PMID: 20079931 |
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 |
Photoreceptor layer topography in children with leber congenital amaurosis caused by RPE65 mutations. | Jacobson SG | Investigative ophthalmology & visual science | 2008 | PMID: 18539930 |
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/a12475a1-7bae-4034-b8bc-f41373cc8110 | - | - | - | - |
Text-mined citations for rs61752909 ...
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.