NM_025114.4(CEP290):c.7283_7286dup (p.Tyr2429Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 10, 2024
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:: RCV001229340.7

Allele description [Variation Report for NM_025114.4(CEP290):c.7283_7286dup (p.Tyr2429Ter)]

NM_025114.4(CEP290):c.7283_7286dup (p.Tyr2429Ter)

Genes:

RLIG1:RNA 5'-phosphate and 3'-OH ligase 1 [Gene - HGNC]
CEP290:centrosomal protein 290 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

12q21.32

Genomic location:

Preferred name:

NM_025114.4(CEP290):c.7283_7286dup (p.Tyr2429Ter)

HGVS:

NC_000012.12:g.88049340_88049343dup
NG_008417.2:g.97876_97879dup
NM_001009894.3:c.*918_*921dupMANE SELECT
NM_025114.4:c.7283_7286dupMANE SELECT
NP_079390.3:p.Tyr2429Ter
LRG_694t1:c.7283_7286dup
LRG_694:g.97876_97879dup
LRG_694p1:p.Tyr2429Ter
NC_000012.11:g.88443114_88443115insTACT
NC_000012.11:g.88443117_88443120dup
NM_025114.3:c.7283_7286dup
NM_025114.3:c.7283_7286dupAGTA

Protein change:

Y2429*

Links:

dbSNP: rs773642187

NCBI 1000 Genomes Browser:

rs773642187

Molecular consequence:

NM_001009894.3:c.*918_*921dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_025114.4:c.7283_7286dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; JOUBERT-BOLTSHAUSER SYNDROME; Joubert syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

Name:: Meckel-Gruber syndrome
Synonyms:: DYSENCEPHALIA SPLANCHNOCYSTICA; GRUBER SYNDROME; Dysencephalia splachnocystica
Identifiers:: MONDO: MONDO:0018921; MedGen: C0265215; OMIM: PS249000

Name:: Nephronophthisis
Synonyms:: Juvenile Nephronophthisis
Identifiers:: MONDO: MONDO:0019005; MedGen: C0687120; OMIM: PS256100; Human Phenotype Ontology: HP:0000090

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001401782	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20683928, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001401782

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2024)

germline

clinical testing

PubMed (2)
[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

Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes.

Coppieters F, Casteels I, Meire F, De Jaegere S, Hooghe S, van Regemorter N, Van Esch H, Matuleviciene A, Nunes L, Meersschaut V, Walraedt S, Standaert L, Coucke P, Hoeben H, Kroes HY, Vande Walle J, de Ravel T, Leroy BP, De Baere E.

Hum Mutat. 2010 Oct;31(10):E1709-66. doi: 10.1002/humu.21336.

PubMed [citation]

PMID:: 20683928
PMCID:: PMC3048164

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. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001401782.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Tyr2429*) in the CEP290 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CEP290 protein. This variant is present in population databases (rs773642187, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 956518). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the CEP290 protein in which other variant(s) (p.Thr2457Alafs*27) have been determined to be pathogenic (PMID: 20683928). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been 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

Last Updated: Mar 11, 2025

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