VCV000993032.7 - ClinVar

NM_025114.4(CEP290):c.4714G>T (p.Glu1572Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_025114.4(CEP290):c.4714G>T (p.Glu1572Ter)

Variation ID: 993032 Accession: VCV000993032.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q21.32 12: 88083945 (GRCh38) [ NCBI UCSC ] 12: 88477722 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 26, 2021	Apr 6, 2024	Mar 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025114.4:c.4714G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079390.3:p.Glu1572Ter	nonsense
NC_000012.12:g.88083945C>A
NC_000012.11:g.88477722C>A
NG_008417.2:g.63272G>T
LRG_694:g.63272G>T
LRG_694t1:c.4714G>T	LRG_694p1:p.Glu1572Ter

... more HGVS ... less HGVS

Protein change

E1572*

Other names

Canonical SPDI

NC_000012.12:88083944:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1292516576 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CEP290		-	-	GRCh38 GRCh37	3683	3860

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Joubert syndrome 5	Pathogenic (1)	no assertion criteria provided	Oct 11, 2020	RCV001283851.1
Familial aplasia of the vermis Meckel-Gruber syndrome Nephronophthisis	Pathogenic (1)	criteria provided, single submitter	Aug 10, 2022	RCV002541764.3
not provided	Likely pathogenic (1)	criteria provided, single submitter	Oct 28, 2022	RCV003135916.3
Leber congenital amaurosis 10	Pathogenic (1)	criteria provided, single submitter	Mar 29, 2024	RCV003989669.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Oct 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826180.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Aug 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial aplasia of the vermis Meckel-Gruber syndrome Nephronophthisis Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003449720.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 22693042‚ 29620724‚ 16909394‚ 17345604‚ 20690115 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 993032). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 993032). This premature translational stop signal has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 22693042, 29620724). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1572*) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). (less)
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 10 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004808200.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Oct 11, 2020)	no assertion criteria provided Method: clinical testing	Joubert syndrome 5 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469287.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 993032). This premature translational stop signal has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 22693042, 29620724). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1572*) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Expanding the phenome and variome of skeletal dysplasia.	Maddirevula S	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29620724
Molecular characterization of Joubert syndrome in Saudi Arabia.	Alazami AM	Human mutation	2012	PMID: 22693042
CEP290, a gene with many faces: mutation overview and presentation of CEP290base.	Coppieters F	Human mutation	2010	PMID: 20690115
Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype.	Perrault I	Human mutation	2007	PMID: 17345604
Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.	den Hollander AI	American journal of human genetics	2006	PMID: 16909394

Text-mined citations for rs1292516576 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_025114.4(CEP290):c.4714G>T (p.Glu1572Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1292516576 ...