NM_000329.3(RPE65):c.1451-1G>A AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 15, 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:: RCV003120686.5

Allele description [Variation Report for NM_000329.3(RPE65):c.1451-1G>A]

NM_000329.3(RPE65):c.1451-1G>A

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.1451-1G>A

HGVS:

NC_000001.11:g.68429928C>T
NG_008472.2:g.25032G>A
NM_000329.3:c.1451-1G>AMANE SELECT
NM_001406853.1:c.1343-1G>A
NM_001406856.1:c.1175-1G>A
NM_001406857.1:c.1175-1G>A
NC_000001.10:g.68895611C>T

Links:

dbSNP: rs1317871521

NCBI 1000 Genomes Browser:

rs1317871521

Molecular consequence:

NM_000329.3:c.1451-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406853.1:c.1343-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406856.1:c.1175-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406857.1:c.1175-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003786327	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 15, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17576681, 9536098, 31273949, 31957135, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003786327

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 15, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

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	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003786327.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. ClinVar contains an entry for this variant (Variation ID: 1321180). Disruption of this splice site has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 31273949, 31957135). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 13 of the RPE65 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

#	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: Sep 29, 2024

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