ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr)
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.1087C>A (p.Pro363Thr)
Variation ID: 13117 Accession: VCV000013117.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68438228 (GRCh38) [ NCBI UCSC ] 1: 68903911 (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 Nov 19, 2016 Feb 28, 2024 Dec 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.1087C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Pro363Thr missense NC_000001.11:g.68438228G>T NC_000001.10:g.68903911G>T NG_008472.2:g.16732C>A Q16518:p.Pro363Thr - Protein change
- P363T
- Other names
- NM_000329.3(RPE65):c.1087C>A
- Canonical SPDI
- NC_000001.11:68438227:G:T
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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), exomes 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 |
937 | 963 |
Conditions - Germline
Condition
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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
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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 (1) |
no assertion criteria provided
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Oct 1, 1997 | RCV000013996.24 | |
Pathogenic (1) |
criteria provided, single submitter
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May 17, 2022 | RCV000815732.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV001250693.3 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 9, 2020 | RCV001826460.1 | |
Pathogenic (1) |
reviewed by expert panel
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Dec 22, 2023 | RCV003460468.1 |
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
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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
(Dec 22, 2023)
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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: SCV004190220.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
The NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is reported in the literature in a homozygous state in at least two probands affected with Leber congenital amaurosis or early … (more)
The NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is reported in the literature in a homozygous state in at least two probands affected with Leber congenital amaurosis or early onset severe retinal dystrophy (1 point, PM3, PMID: 9326941, PMID: 26352687). At least one patient harboring the variant exhibited reduced or nondetectable rod ERG (required, 0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), light staring (1 pt), nyctalopia (0.5 pts), and positive response to RPE65 gene therapy (8 pts), which together are specific for RPE65-related recessive retinopathy (13 pts total, VCEP member-provided data, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy in multiple families with at least 3 members (PP1_strong, PMID:9326941, PMID: 26352687). This variant is reported in ClinVar (Variation ID: 13117), and its Popmax Filtering AF in gnomAD v.2.1.1 is 0.00004443 (4/30608 alleles) in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP threshold (<0.0002) (PM2_Supporting). The meta-predictor REVEL gives a score of 0.702, which is above the ClinGen LCA/eoRD VCEP PP3 threshold of >0.644 and predicts a damaging effect on RPE65 function (PP3). An in vitro isomerohydrolase activity assay performed in adenovirus-infected 293A-LRAT cells showed that the p.Pro363Thr mutant exhibits complete loss of 11-cis-retinol production relative to the wild-type RPE65 control, confirming that this variant has a damaging effect on protein function (PMID: 16828753, 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: PP1_Strong, PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
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Pathogenic
(Oct 19, 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: SCV004209215.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 28, 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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MGZ Medical Genetics Center
Accession: SCV002578891.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(May 17, 2022)
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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: SCV000956201.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 363 of the RPE65 protein (p.Pro363Thr). … (more)
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 363 of the RPE65 protein (p.Pro363Thr). This variant is present in population databases (rs121917744, gnomAD 0.01%). This missense change has been observed in individuals with Leber congenital amaurosis and retinal dystrophy (PMID: 9326941, 15024725, 29332120). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13117). 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. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16828753). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 1997)
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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: SCV000034243.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2016 |
Comment on evidence:
In a consanguineous Indian family (PMK30) in which 4 individuals had autosomal recessive childhood-onset severe retinal dystrophy, Gu et al. (1997) mapped the disease locus, … (more)
In a consanguineous Indian family (PMK30) in which 4 individuals had autosomal recessive childhood-onset severe retinal dystrophy, Gu et al. (1997) mapped the disease locus, which they designated RP20 (613794), to chromosome 1p31-p22. Gu et al. (1997) found that all 4 affected individuals were homozygous for a 1141C-A transversion in the RPE65 gene. The 4 parents were heterozygous for the sequence change, as were 3 of the 4 unaffected sibs; the fourth unaffected sib carried only the wildtype sequence. The mutation predicted a nonconservative replacement of the evolutionarily conserved proline-363 by threonine (P363T). The onset of severe visual impairment in this family varied between 3 and 7 years of age. Night blindness was a typical and early symptom in all patients. Most patients became severely visually handicapped between 5 and 12 years of age and could only count fingers at 1 to 3 meters distance or were able to see only hand movements. The 4 patients varied in age from 20 to 32 years. Two had nystagmus, which was consistent with an early onset of severe visual disability. Fundus examination showed attenuated vessels and atrophy of the optic disc. Although bone-spicule formation was not a typical feature, many whitish dots were compatible with extensive RPE defects. (less)
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Pathogenic
(Nov 09, 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: SCV002092744.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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: SCV001425566.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Number of individuals with the variant: 2
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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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Severe Loss of Tritan Color Discrimination in RPE65 Associated Leber Congenital Amaurosis. | Kumaran N | Investigative ophthalmology & visual science | 2018 | PMID: 29332120 |
Impacts of two point mutations of RPE65 from Leber's congenital amaurosis on the stability, subcellular localization and isomerohydrolase activity of RPE65. | Chen Y | FEBS letters | 2006 | PMID: 16828753 |
Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. | Hanein S | Human mutation | 2004 | PMID: 15024725 |
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/2a06ba5b-9a33-453f-9155-c4652c7b97b3 | - | - | - | - |
Text-mined citations for rs121917744 ...
HelpRecord last updated Feb 28, 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.