NM_000329.3(RPE65):c.495+1dup AND RPE65-related recessive retinopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 22, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003460769.1

Allele description [Variation Report for NM_000329.3(RPE65):c.495+1dup]

NM_000329.3(RPE65):c.495+1dup

Gene:

RPE65:retinoid isomerohydrolase RPE65 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1p31.3

Genomic location:

Preferred name:

NM_000329.3(RPE65):c.495+1dup

HGVS:

NC_000001.11:g.68444531dup
NG_008472.2:g.10430dup
NM_000329.3:c.495+1dupMANE SELECT
NM_001406853.1:c.387+1dup
NM_001406856.1:c.219+1dup
NM_001406857.1:c.219+1dup
NM_001406859.1:c.495+1dup
NM_001406860.1:c.496dup
NP_001393789.1:p.Val166fs
NC_000001.10:g.68910212_68910213insC
NC_000001.10:g.68910214dup
NM_000329.2:c.495_495+1insG

Protein change:

V166fs

Links:

dbSNP: rs281865288

NCBI 1000 Genomes Browser:

rs281865288

Molecular consequence:

NM_001406860.1:c.496dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000329.3:c.495+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406853.1:c.387+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406856.1:c.219+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406857.1:c.219+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406859.1:c.495+1dup - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: RPE65-related recessive retinopathy
Synonyms:: Recessive RPE65 retinopathy
Identifiers:: MONDO: MONDO:0100368; MedGen: CN305526

Recent activity

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hypothetical protein Naga_100066g26 [Nannochloropsis gaditana]
hypothetical protein Naga_100066g26 [Nannochloropsis gaditana]
gi|585102876|gb|EWM22375.1||gnl|WGS |Naga_100066g26.10332

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004190227	ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen LCAeoRD ACMG Specifications RPE65 V1.0.0)	Pathogenic (Dec 22, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004190227

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen LCAeoRD ACMG Specifications RPE65 V1.0.0)

Pathogenic
(Dec 22, 2023)

germline

curation

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Details of each submission

From ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen, SCV004190227.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000329.3(RPE65): c.495+1dup variant disrupts a canonical splice site in intron 5 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMID: 26656277). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy, one of whom was compound heterozygous with the c.130C>T p.Arg44Ter variant confirmed in trans (1 pt, PMID: 26626312) which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). This variant is absent from gnomAD v2.1.1 (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: PVS1, PM3_strong, PM2_supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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