ClinVar Genomic variation as it relates to human health
NM_201253.3(CRB1):c.2842T>C (p.Cys948Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_201253.3(CRB1):c.2842T>C (p.Cys948Arg)
Variation ID: 427863 Accession: VCV000427863.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q31.3 1: 197429614 (GRCh38) [ NCBI UCSC ] 1: 197398744 (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 Dec 3, 2017 Mar 30, 2024 Jan 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_201253.3:c.2842T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_957705.1:p.Cys948Arg missense NM_001193640.2:c.2506T>C NP_001180569.1:p.Cys836Arg missense NM_001257965.2:c.2770T>C NP_001244894.1:p.Cys924Arg missense NM_001257966.2:c.2129-5986T>C intron variant NR_047563.2:n.2795T>C non-coding transcript variant NR_047564.2:n.3003T>C non-coding transcript variant NC_000001.11:g.197429614T>C NC_000001.10:g.197398744T>C NG_008483.2:g.233153T>C - Protein change
- C948R, C924R, C836R
- Other names
- -
- Canonical SPDI
- NC_000001.11:197429613:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
-
Global minor allele
frequency (GMAF) HelpThe 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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
---|---|---|---|---|---|---|
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 |
1902 | 1926 |
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. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
May 9, 2017 | RCV000515691.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 28, 2019 | RCV000986493.1 | |
Pathogenic (2) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV001250609.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 24, 2023 | RCV001389640.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2023 | RCV001836643.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV003449270.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV003987563.1 |
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
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135505.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Pathogenic
(Feb 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pigmented paravenous retinochoroidal atrophy
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002097295.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Comment:
The c.2842T>C;p.(Cys948Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 427863; PMID: 28819299; 28005958) - … (more)
The c.2842T>C;p.(Cys948Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 427863; PMID: 28819299; 28005958) - PS4. This variant is not present in population databases (rs62645747, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Cys948Arg) was detected in trans with a pathogenic variant (PMID: 28819299; 28005958) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 8
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004180089.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pigmented paravenous retinochoroidal atrophy
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004180090.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 12
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004180091.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Pathogenic
(Oct 24, 2023)
|
criteria provided, single submitter
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
|
Invitae
Accession: SCV001591071.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 948 of the CRB1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 948 of the CRB1 protein (p.Cys948Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinal dystrophies (PMID: 28005958, 28714225, 28819299). ClinVar contains an entry for this variant (Variation ID: 427863). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Cys948 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10508521, 18055816, 19401883, 20956273, 23379534, 24512366, 27113771). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803655.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: CRB1 c.2842T>C (p.Cys948Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CRB1 c.2842T>C (p.Cys948Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251092 control chromosomes (gnomAD). c.2842T>C has been reported in the literature in multiple individuals affected with Retinal Dystrophy (Tiwari_2016, deCastro-Mir_2016, Motta_2017, Soens_2017, Sallum_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28819299, 32865313, 28714225, 27353947, 28005958). ClinVar contains an entry for this variant (Variation ID: 427863). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(May 09, 2017)
|
no assertion criteria provided
Method: research
|
Leber congenital amaurosis
Affected status: yes
Allele origin:
germline
|
Rui Chen Lab, Baylor College of Medicine
Accession: SCV000579415.1
First in ClinVar: Dec 03, 2017 Last updated: Dec 03, 2017
Comment:
An in vitrominigene system was used to confirm that the variant disrupts splicing
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Leber congenital amaurosis 8
Affected status: yes
Allele origin:
inherited
|
Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001425477.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Number of individuals with the variant: 2
|
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
sequence_variant_affecting_splicing
|
|
|
Rui Chen Lab, Baylor College of Medicine
Accession: SCV000579415.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients. | Sallum JMF | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 32865313 |
The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes. | Motta FL | Scientific reports | 2017 | PMID: 28819299 |
Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. | Soens ZT | Human mutation | 2017 | PMID: 28714225 |
Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing. | de Castro-Miró M | PloS one | 2016 | PMID: 28005958 |
Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies. | Tiwari A | Scientific reports | 2016 | PMID: 27353947 |
Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants. | Kousal B | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2016 | PMID: 27113771 |
Retinal Dystrophy with Intraretinal Cystoid Spaces Associated with Mutations in the Crumbs Homologue (CRB1) Gene. | Cordovez JA | Ophthalmic genetics | 2015 | PMID: 24512366 |
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 |
Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. | Henderson RH | The British journal of ophthalmology | 2011 | PMID: 20956273 |
Case report: autofluorescence imaging and phenotypic variance in a sibling pair with early-onset retinal dystrophy due to defective CRB1 function. | Tosi J | Current eye research | 2009 | PMID: 19401883 |
Mutation screening of 299 Spanish families with retinal dystrophies by Leber congenital amaurosis genotyping microarray. | Vallespin E | Investigative ophthalmology & visual science | 2007 | PMID: 18055816 |
Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). | den Hollander AI | Nature genetics | 1999 | PMID: 10508521 |
click to load more click to collapse |
Text-mined citations for rs62645747 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.