NM_025114.4(CEP290):c.7331del (p.Lys2444fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 4, 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:: RCV002912902.4

Allele description [Variation Report for NM_025114.4(CEP290):c.7331del (p.Lys2444fs)]

NM_025114.4(CEP290):c.7331del (p.Lys2444fs)

Genes:

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

Variant type:

Deletion

Cytogenetic location:

12q21.32

Genomic location:

Preferred name:

NM_025114.4(CEP290):c.7331del (p.Lys2444fs)

HGVS:

NC_000012.12:g.88049294del
NG_008417.2:g.97924del
NM_001009894.3:c.*872delMANE SELECT
NM_025114.4:c.7331delMANE SELECT
NP_079390.3:p.Lys2444fs
LRG_694t1:c.7331del
LRG_694:g.97924del
LRG_694p1:p.Lys2444fs
NC_000012.11:g.88443070del
NC_000012.11:g.88443071del

Protein change:

K2444fs

Links:

dbSNP: rs2499339598

NCBI 1000 Genomes Browser:

rs2499339598

Molecular consequence:

NM_001009894.3:c.*872del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_025114.4:c.7331del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Joubert syndrome
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; JOUBERT-BOLTSHAUSER SYNDROME; Familial aplasia of the vermis
Identifiers:: MONDO: MONDO:0018772; MedGen: C5979921; 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
SCV003248018	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16682973, 16909394, 29588463, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003248018

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 4, 2023)

germline

clinical testing

PubMed (4)
[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

The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.

Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, et al.

Nat Genet. 2006 Jun;38(6):674-81. Epub 2006 May 7.

PubMed [citation]

PMID:: 16682973

Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.

den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP.

Am J Hum Genet. 2006 Sep;79(3):556-61. Epub 2006 Jul 11.

PubMed [citation]

PMID:: 16909394
PMCID:: PMC1559533

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003248018.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CEP290 protein in which other variant(s) (p.Leu2448Thrfs*8) have been determined to be pathogenic (PMID: 16682973, 16909394, 29588463). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2041164). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2444Argfs*2) in the CEP290 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the CEP290 protein.

#	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: Dec 14, 2025

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