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NM_000329.3(RPE65):c.1459del (p.Val486_Leu487insTer) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 24, 2022
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:
RCV002847075.2

Allele description [Variation Report for NM_000329.3(RPE65):c.1459del (p.Val486_Leu487insTer)]

NM_000329.3(RPE65):c.1459del (p.Val486_Leu487insTer)

Gene:
RPE65:retinoid isomerohydrolase RPE65 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p31.3
Genomic location:
Preferred name:
NM_000329.3(RPE65):c.1459del (p.Val486_Leu487insTer)
HGVS:
  • NC_000001.11:g.68429919del
  • NG_008472.2:g.25041del
  • NM_000329.3:c.1459delMANE SELECT
  • NM_001406853.1:c.1351delC
  • NM_001406856.1:c.1183delC
  • NM_001406857.1:c.1183delC
  • NP_000320.1:p.Val486_Leu487insTer
  • NP_001393782.1:p.Leu451Terfs
  • NP_001393785.1:p.Leu395Terfs
  • NP_001393786.1:p.Leu395Terfs
  • NC_000001.10:g.68895602del
Molecular consequence:
  • NM_001406853.1:c.1351delC - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406856.1:c.1183delC - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406857.1:c.1183delC - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000329.3:c.1459del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001406853.1:c.1351delC - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001406856.1:c.1183delC - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001406857.1:c.1183delC - nonsense - [Sequence Ontology: SO:0001587]

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003224429Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 24, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.

Stone EM.

Am J Ophthalmol. 2007 Dec;144(6):791-811. Epub 2007 Oct 26.

PubMed [citation]
PMID:
17964524

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV003224429.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RPE65 protein in which other variant(s) (p.Tyr501Profs*10) have been determined to be pathogenic (PMID: 17964524; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with RPE65-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu487*) in the RPE65 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the RPE65 protein.

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

Last Updated: Feb 28, 2024