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NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 4, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001068036.5

Allele description [Variation Report for NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly)]

NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly)

Gene:
RPE65:retinoid isomerohydrolase RPE65 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p31.3
Genomic location:
Preferred name:
NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly)
HGVS:
  • NC_000001.11:g.68431085T>C
  • NG_008472.2:g.23875A>G
  • NM_000329.3:c.1430A>GMANE SELECT
  • NP_000320.1:p.Asp477Gly
  • NC_000001.10:g.68896768T>C
  • NG_008472.1:g.23875A>G
  • NM_000329.2:c.1430A>G
Protein change:
D477G; ASP477GLY
Links:
OMIM: 180069.0013; dbSNP: rs1571158279
NCBI 1000 Genomes Browser:
rs1571158279
Molecular consequence:
  • NM_000329.3:c.1430A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Leber congenital amaurosis 2 (LCA2)
Synonyms:
AMAUROSIS CONGENITA OF LEBER II; Amaurosis congenita of Leber, type 2; RPE65-Related Leber Congenital Amaurosis
Identifiers:
MONDO: MONDO:0008765; MedGen: C1859844; Orphanet: 65; OMIM: 204100
Name:
Retinitis pigmentosa 20 (RP20)
Synonyms:
RP 20
Identifiers:
MONDO: MONDO:0013425; MedGen: C3151086; Orphanet: 791; OMIM: 613794

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001233124Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Nov 4, 2023)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The clinical features of retinal disease due to a dominant mutation in RPE65.

Hull S, Mukherjee R, Holder GE, Moore AT, Webster AR.

Mol Vis. 2016;22:626-35.

PubMed [citation]
PMID:
27307694
PMCID:
PMC4901053

Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa.

Jauregui R, Park KS, Tsang SH.

Ophthalmic Genet. 2018 Aug;39(4):544-549. doi: 10.1080/13816810.2018.1484929.

PubMed [citation]
PMID:
29947567
PMCID:
PMC6314189
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001233124.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 477 of the RPE65 protein (p.Asp477Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinal dystrophy with choroidal involvement (PMID: 21654732, 27307694, 29947567). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 750796). 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 not expected to disrupt RPE65 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 21654732, 28041994, 29659842, 30628748). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024