ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser)
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.1338G>T (p.Arg446Ser)
Variation ID: 427864 Accession: VCV000427864.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68431282 (GRCh38) [ NCBI UCSC ] 1: 68896965 (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 Dec 3, 2017 Feb 28, 2024 Feb 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.1338G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Arg446Ser missense NC_000001.11:g.68431282C>A NC_000001.10:g.68896965C>A NG_008472.2:g.23678G>T - Protein change
- R446S
- Other names
- NM_000329.3(RPE65):c.1338G>T
- p.Arg446Ser
- Canonical SPDI
- NC_000001.11:68431281:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
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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 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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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Likely pathogenic (2) |
criteria provided, single submitter
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Jun 1, 2018 | RCV000515733.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2022 | RCV001245608.5 | |
Pathogenic (1) |
reviewed by expert panel
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Feb 20, 2024 | RCV003766756.1 |
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
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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: SCV004697405.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
NM_000329.3(RPE65):c.1338G>T is a missense variant that substitutes arginine with serine at position 446. The variant is found in multiple probands affected with early-onset severe retinal … (more)
NM_000329.3(RPE65):c.1338G>T is a missense variant that substitutes arginine with serine at position 446. The variant is found in multiple probands affected with early-onset severe retinal dystrophy. At least one patient genotyped by whole exome sequencing (2 pts) has a diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), and flat rod (0.5 pts) and cone (1 pt) ERG responses, which together are highly specific for RPE65-related recessive retinopathy (9.5 pts, PMID: 30870047, PP4_Moderate). At least 3 reported probands harbor the variant in the homozygous state, while an additional proband harbors this maternal variant in compound heterozygosity with a paternal c.361dup (p.Ser121Phefs*10 variant (previously classified pathogenic by the ClinGen LCA/eoRD VCEP)(PMID: 30870047, PM3_Strong). Three pairs of siblings have been reported (PMID: 30870047) harboring the variant in either the homozygous or compound heterozygous state (PP1). This variant has a Grpmax Filtering AF of 0.000009610 (2/34488, with no homozygotes) in the Latino/Admixed American population in gnomAD v2.1.1 which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002. Although the meta-predictor REVEL gives a score of 0.571, which is below the ClinGen LCA/eoRD VCEP PP3 threshold of >0.7, the computational splicing predictor SpliceAI indicates that the variant triggers the loss of a splice donor site, with a change score of 0.45. The variant was confirmed to exhibit a complete splicing defect in two minigene assays relative to the wild-type control, showing skipping of the 95-bp exon 12, indicating that it triggers nonsense-mediated decay (PMID: 30996589, PMID: 28714225, PVS1). 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_Strong, PP1, PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023) (less)
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Likely pathogenic
(Jun 01, 2018)
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criteria provided, single submitter
Method: research
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Leber congenital amaurosis
Affected status: yes
Allele origin:
inherited
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Cytogenetics and Genomics Laboratory, Medical University of South Carolina
Accession: SCV000803382.1
First in ClinVar: Dec 03, 2017 Last updated: Dec 03, 2017 |
Number of individuals with the variant: 19
Geographic origin: Central America
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Pathogenic
(Nov 08, 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: SCV001418906.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This variant is present in population databases (no rsID available, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt … (more)
This variant is present in population databases (no rsID available, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 427864). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 26047050, 28714225, 30870047). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 446 of the RPE65 protein (p.Arg446Ser). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. (less)
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Pathogenic
(May 09, 2017)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis
Affected status: yes
Allele origin:
germline
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Rui Chen Lab, Baylor College of Medicine
Accession: SCV000579419.1
First in ClinVar: Dec 03, 2017 Last updated: Dec 03, 2017 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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sequence_variant_affecting_splicing
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Rui Chen Lab, Baylor College of Medicine
Accession: SCV000579419.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy. | Glen WB Jr | Ophthalmic genetics | 2019 | PMID: 30870047 |
Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. | Soens ZT | Human mutation | 2017 | PMID: 28714225 |
Comprehensive Molecular Diagnosis of a Large Chinese Leber Congenital Amaurosis Cohort. | Wang H | Investigative ophthalmology & visual science | 2015 | PMID: 26047050 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/79b802a8-f024-4536-a8a2-3e73fddaa67c | - | - | - | - |
Text-mined citations for rs1420672586 ...
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.