VCV002202906.3 - ClinVar

NM_201253.3(CRB1):c.138del (p.Asp47fs)

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.

(2)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_201253.3(CRB1):c.138del (p.Asp47fs)

Variation ID: 2202906 Accession: VCV002202906.3

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1q31.3 1: 197328487 (GRCh38) [ NCBI UCSC ] 1: 197297617 (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	Feb 8, 2023	Jun 17, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_201253.3:c.138del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_957705.1:p.Asp47fs	frameshift
NM_001193640.2:c.138del	NP_001180569.1:p.Asp47fs	frameshift
NM_001257965.2:c.-70del		5 prime UTR
NM_001257966.2:c.138del	NP_001244895.1:p.Asp47fs	frameshift
NR_047563.2:n.299del		non-coding transcript variant
NR_047564.2:n.299del		non-coding transcript variant
NC_000001.11:g.197328489del
NC_000001.10:g.197297619del
NG_008483.3:g.131987del

... more HGVS ... less HGVS

Protein change

D47fs

Other names

Canonical SPDI

NC_000001.11:197328486:AAA:AA

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

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.
CRB1		-	-	GRCh38 GRCh37	1942	1967

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.
Leber congenital amaurosis 8 Retinitis pigmentosa 12	Pathogenic (1)	criteria provided, single submitter	Jan 5, 2022	RCV002664199.3
Leber congenital amaurosis 8	Pathogenic (1)	criteria provided, single submitter	Nov 27, 2023	RCV004572809.1

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.
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 8 Retinitis pigmentosa 12 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: SCV003523369.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (9) PubMed: 24535598‚ 27806333‚ 10508521‚ 22065545‚ 23379534‚ 25412400‚ 26957898‚ 28041643‚ 29391521 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with inherited retinal dystrophy (PMID: … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with inherited retinal dystrophy (PMID: 24535598, 27806333). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp47Ilefs*24) in the CRB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB1 are known to be pathogenic (PMID: 10508521, 22065545, 23379534, 25412400, 26957898, 28041643, 29391521). (less)
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005058566.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with inherited retinal dystrophy (PMID: 24535598, 27806333). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp47Ilefs*24) in the CRB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB1 are known to be pathogenic (PMID: 10508521, 22065545, 23379534, 25412400, 26957898, 28041643, 29391521).

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
A clinical and molecular characterisation of CRB1-associated maculopathy.	Khan KN	European journal of human genetics : EJHG	2018	PMID: 29391521
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
Novel mutations in CRB1 gene identified in a chinese pedigree with retinitis pigmentosa by targeted capture and next generation sequencing.	Lu L	Oncotarget	2016	PMID: 27806333
Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies.	Oishi M	Molecular vision	2016	PMID: 26957898
Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.	Consugar MB	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25412400
Detection of CRB1 mutations in families with retinal dystrophy through phenotype-oriented mutational screening.	Li S	International journal of molecular medicine	2014	PMID: 24535598
High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population.	Corton M	Orphanet journal of rare diseases	2013	PMID: 23379534
CRB1 mutations in inherited retinal dystrophies.	Bujakowska K	Human mutation	2012	PMID: 22065545
Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).	den Hollander AI	Nature genetics	1999	PMID: 10508521

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_201253.3(CRB1):c.138del (p.Asp47fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...