NM_025114.4(CEP290):c.5777G>C (p.Arg1926Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 23, 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:: RCV000815985.6

Allele description [Variation Report for NM_025114.4(CEP290):c.5777G>C (p.Arg1926Pro)]

NM_025114.4(CEP290):c.5777G>C (p.Arg1926Pro)

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.5777G>C (p.Arg1926Pro)

Other names:

NP_079390.3:p.(Arg1926Pro)

HGVS:

NC_000012.12:g.88071859C>G
NG_008417.2:g.75358G>C
NM_025114.4:c.5777G>CMANE SELECT
NP_079390.3:p.Arg1926Pro
NP_079390.3:p.Arg1926Pro
LRG_694t1:c.5777G>C
LRG_694:g.75358G>C
LRG_694p1:p.Arg1926Pro
NC_000012.11:g.88465636C>G
NG_008417.1:g.75358G>C
NM_025114.3:c.5777G>C

Protein change:

R1926P

Links:

dbSNP: rs778030031

NCBI 1000 Genomes Browser:

rs778030031

Molecular consequence:

NM_025114.4:c.5777G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; 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
SCV000956469	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21153841, 29398085, 31630094, 32865313, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000956469

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 23, 2023)

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

Potential involvement of more than one locus in trait manifestation for individuals with Leber congenital amaurosis.

Wiszniewski W, Lewis RA, Stockton DW, Peng J, Mardon G, Chen R, Lupski JR.

Hum Genet. 2011 Mar;129(3):319-27. doi: 10.1007/s00439-010-0928-y. Epub 2010 Dec 14.

PubMed [citation]

PMID:: 21153841
PMCID:: PMC3625363

Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies.

Sheck L, Davies WIL, Moradi P, Robson AG, Kumaran N, Liasis AC, Webster AR, Moore AT, Michaelides M.

Ophthalmology. 2018 Jun;125(6):894-903. doi: 10.1016/j.ophtha.2017.12.013. Epub 2018 Feb 3.

PubMed [citation]

PMID:: 29398085
PMCID:: PMC5974693

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000956469.6

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

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1926 of the CEP290 protein (p.Arg1926Pro). This variant is present in population databases (rs778030031, gnomAD 0.0009%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 21153841, 29398085, 31630094, 32865313). 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. ClinVar contains an entry for this variant (Variation ID: 659046). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CEP290 protein function with a positive predictive value of 80%. 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: May 7, 2024

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