NM_025114.4(CEP290):c.4962_4963del (p.Glu1656fs) AND CEP290-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 21, 2021
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:: RCV001420744.4

Allele description [Variation Report for NM_025114.4(CEP290):c.4962_4963del (p.Glu1656fs)]

NM_025114.4(CEP290):c.4962_4963del (p.Glu1656fs)

Gene:

CEP290:centrosomal protein 290 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12q21.32

Genomic location:

Preferred name:

NM_025114.4(CEP290):c.4962_4963del (p.Glu1656fs)

HGVS:

NC_000012.12:g.88083081_88083082del
NG_008417.2:g.64136_64137del
NM_025114.4:c.4962_4963delMANE SELECT
NP_079390.3:p.Glu1656fs
LRG_694t1:c.4962_4963del
LRG_694:g.64136_64137del
LRG_694p1:p.Glu1656fs
NC_000012.11:g.88476857_88476858del
NC_000012.11:g.88476858_88476859del
NG_008417.1:g.64136_64137del
NM_025114.3:c.4962_4963delAA
NM_025114.4:c.4962_4963delAAMANE SELECT

Protein change:

E1656fs

Links:

dbSNP: rs764309755

NCBI 1000 Genomes Browser:

rs764309755

Molecular consequence:

NM_025114.4:c.4962_4963del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001623087	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 21, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29482223, 20690115, 17345604, 32865313, 21153841 Citation Link,
SCV004117154	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Jun 14, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001623087

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 21, 2021)

germline

clinical testing

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

Citation Link,

SCV004117154

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Jun 14, 2024)

germline

clinical testing

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

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.

Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine CS, Mochel F, Labauge P, Ewenczyk C, Ding J, Gibbs JR, Hannequin D, Melki J, Toutain A, Laugel V, Forlani S, Charles P, Broussolle E, Thobois S, Afenjar A, Anheim M, Calvas P, Castelnovo G, et al.

JAMA Neurol. 2018 May 1;75(5):591-599. doi: 10.1001/jamaneurol.2017.5121.

PubMed [citation]

PMID:: 29482223
PMCID:: PMC5885259

CEP290, a gene with many faces: mutation overview and presentation of CEP290base.

Coppieters F, Lefever S, Leroy BP, De Baere E.

Hum Mutat. 2010 Oct;31(10):1097-108. doi: 10.1002/humu.21337. Review.

PubMed [citation]

PMID:: 20690115

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623087.1

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

Description

Variant summary: CEP290 c.4962_4963delAA (p.Glu1656AsnfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 140738 control chromosomes. c.4962_4963delAA has been reported in the literature in multiple compound heterozygous individuals affected with Leber Congenital Amaurosis (LCA; e.g. Perrualt_2007, Wiszniewski_2011, Sallum_2020). These data indicate that the variant is likely to be associated with disease. The variant has also been reported in an individual affected with cerebellar ataxia (e.g. Coutellier_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From PreventionGenetics, part of Exact Sciences, SCV004117154.2

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

Description

The CEP290 c.4962_4963delAA variant is predicted to result in a frameshift and premature protein termination (p.Glu1656Asnfs*3). This variant has been reported as causative for Leber congenital amaurosis (see for examples: Perrault et al. 2007. PubMed ID: 17345604; Sallum et al. 2020. PubMed ID: 32865313; Testa et al. 2021. PubMed ID: 34196655). This variant is reported in 0.0088% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.

#	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: Nov 24, 2024

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