VCV002928516.2 - ClinVar

NM_201253.3(CRB1):c.1623C>A (p.Tyr541Ter)

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/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_201253.3(CRB1):c.1623C>A (p.Tyr541Ter)

Variation ID: 2928516 Accession: VCV002928516.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q31.3 1: 197421451 (GRCh38) [ NCBI UCSC ] 1: 197390581 (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 29, 2024	Jun 17, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_201253.3:c.1623C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_957705.1:p.Tyr541Ter	nonsense
NM_001193640.2:c.1287C>A	NP_001180569.1:p.Tyr429Ter	nonsense
NM_001257965.2:c.1416C>A	NP_001244894.1:p.Tyr472Ter	nonsense
NM_001257966.2:c.1623C>A	NP_001244895.1:p.Tyr541Ter	nonsense
NR_047563.2:n.1784C>A		non-coding transcript variant
NR_047564.2:n.1784C>A		non-coding transcript variant
NC_000001.11:g.197421451C>A
NC_000001.10:g.197390581C>A
NG_008483.2:g.224990C>A
NG_008483.3:g.224949C>A

... more HGVS ... less HGVS

Protein change

Y429*, Y472*, Y541*

Other names

Canonical SPDI

NC_000001.11:197421450: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

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	1943	1968

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 23, 2022	RCV003789290.2
Leber congenital amaurosis 8	Likely pathogenic (1)	criteria provided, single submitter	Mar 27, 2024	RCV004573312.1

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 (Dec 23, 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: SCV004574804.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 10508521‚ 22065545‚ 23379534‚ 25412400‚ 26957898‚ 28041643‚ 29391521 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CRB1-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CRB1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Tyr541*) 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)
Likely pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005058541.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CRB1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Tyr541*) 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
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
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 30, 2024

ClinVar Genomic variation as it relates to human health

NM_201253.3(CRB1):c.1623C>A (p.Tyr541Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...