VCV003247806.1 - ClinVar

NC_000001.10:g.(?_197404386)_(197410804_?)del

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000001.10:g.(?_197404386)_(197410804_?)del

Variation ID: 3247806 Accession: VCV003247806.1

Type and length

Deletion, 6,419 bp

Location

Cytogenetic: 1q31.3 1: 197404386-197410804 (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	Jun 30, 2024	Jun 29, 2024	Dec 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_000001.10:g.(?_197404386)_(197410804_?)del

Protein change

Other names

Canonical SPDI

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	1948	1973

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	Dec 5, 2023	RCV004584090.2

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.
Pathogenic (Dec 05, 2023)	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: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005066484.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: PubMed (11) PubMed: 16199547‚ 10508521‚ 22065545‚ 23379534‚ 25412400‚ 26957898‚ 28041643‚ 29391521‚ 24535598‚ 26047050‚ 28129017 Comment: This variant results in the deletion of exon 10 and part of exon 9 (c.3393_3879-492del) of the CRB1 gene. It is expected to disrupt RNA … (more) This variant results in the deletion of exon 10 and part of exon 9 (c.3393_3879-492del) of the CRB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CRB1 are known to be pathogenic (PMID: 10508521, 22065545, 23379534, 25412400, 26957898, 28041643, 29391521). This variant has not been reported in the literature in individuals affected with CRB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 940575). This variant disrupts a region of the CRB1 protein in which other variant(s) (p.Cys1163Phe) have been determined to be pathogenic (PMID: 24535598, 26047050, 28129017). 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. (less)

Comment:

This variant results in the deletion of exon 10 and part of exon 9 (c.3393_3879-492del) of the CRB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CRB1 are known to be pathogenic (PMID: 10508521, 22065545, 23379534, 25412400, 26957898, 28041643, 29391521). This variant has not been reported in the literature in individuals affected with CRB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 940575). This variant disrupts a region of the CRB1 protein in which other variant(s) (p.Cys1163Phe) have been determined to be pathogenic (PMID: 24535598, 26047050, 28129017). 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.

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
Retinal capillaritis in a CRB1-associated retinal dystrophy.	Murro V	Ophthalmic genetics	2017	PMID: 28129017
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
Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies.	Oishi M	Molecular vision	2016	PMID: 26957898
Comprehensive Molecular Diagnosis of a Large Chinese Leber Congenital Amaurosis Cohort.	Wang H	Investigative ophthalmology & visual science	2015	PMID: 26047050
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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).	den Hollander AI	Nature genetics	1999	PMID: 10508521
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Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NC_000001.10:g.(?_197404386)_(197410804_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...