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NM_025114.4(CEP290):c.4813-2A>G AND CEP290-related disorder

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Dec 8, 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:
RCV002222534.4

Allele description [Variation Report for NM_025114.4(CEP290):c.4813-2A>G]

NM_025114.4(CEP290):c.4813-2A>G

Gene:
CEP290:centrosomal protein 290 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q21.32
Genomic location:
Preferred name:
NM_025114.4(CEP290):c.4813-2A>G
HGVS:
  • NC_000012.12:g.88083232T>C
  • NG_008417.2:g.63985A>G
  • NM_025114.4:c.4813-2A>GMANE SELECT
  • LRG_694t1:c.4813-2A>G
  • LRG_694:g.63985A>G
  • NC_000012.11:g.88477009T>C
  • NM_025114.3:c.4813-2A>G
Links:
dbSNP: rs369523378
NCBI 1000 Genomes Browser:
rs369523378
Molecular consequence:
  • NM_025114.4:c.4813-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
CEP290-related disorder
Synonyms:
CEP290-Related Disorders; CEP290-related condition
Identifiers:
MedGen: CN239314

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002500607Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Dec 8, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004118526PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Likely pathogenic
(Sep 6, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Citations

PubMed

Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases.

Martin-Merida I, Avila-Fernandez A, Del Pozo-Valero M, Blanco-Kelly F, Zurita O, Perez-Carro R, Aguilera-Garcia D, Riveiro-Alvarez R, Arteche A, Trujillo-Tiebas MJ, Tahsin-Swafiri S, Rodriguez-Pinilla E, Lorda-Sanchez I, Garcia-Sandoval B, Corton M, Ayuso C.

Ophthalmology. 2019 Aug;126(8):1181-1188. doi: 10.1016/j.ophtha.2019.03.018. Epub 2019 Mar 20.

PubMed [citation]
PMID:
30902645

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500607.2

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

Description

Variant summary: CEP290 c.4813-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7e-05 in 86284 control chromosomes (gnomAD). c.4813-2A>G has been reported in the literature as a homozygous genotype in at-least one Spanish individual affected with an Inherited Retinal Disease (IRD) phenotype who also harbored another reportedly pathogenic homozygous variant in the NR2E3 gene (c.731del) presenting with clinical features characteristic of two different phenotypic entities (Martin-Merida_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV004118526.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The CEP290 c.4813-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. While this variant disrupts the canonical splice acceptor site, it is also predicted to activate a cryptic splice acceptor site 15 nucleotides into the exon (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). The activation of the cryptic splice site is predicted to delete 5 amino acids. This variant has been reported in the homozygous state in an individual with retinitis pigmentosa; however, this individual also harbored a homozygous NR2E3 frameshift variant (Family RP-2350 in Figure S4, Martin-Merida et al. 2019. PubMed ID: 30902645). This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD, indicating it is relatively common in this population. This variant is interpreted as likely pathogenic.

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

Last Updated: Nov 24, 2024