ClinVar Genomic variation as it relates to human health
NM_201253.3(CRB1):c.2290C>T (p.Arg764Cys)
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
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NM_201253.3(CRB1):c.2290C>T (p.Arg764Cys)
Variation ID: 5732 Accession: VCV000005732.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q31.3 1: 197427615 (GRCh38) [ NCBI UCSC ] 1: 197396745 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 20, 2014 May 12, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_201253.3:c.2290C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_957705.1:p.Arg764Cys missense NM_001193640.2:c.1954C>T NP_001180569.1:p.Arg652Cys missense NM_001257965.2:c.2083C>T NP_001244894.1:p.Arg695Cys missense NM_001257966.2:c.2128+5659C>T intron variant NR_047563.2:n.2243C>T non-coding transcript variant NR_047564.2:n.2451C>T non-coding transcript variant NC_000001.11:g.197427615C>T NC_000001.10:g.197396745C>T NG_008483.2:g.231154C>T P82279:p.Arg764Cys - Protein change
- R764C, R652C, R695C
- Other names
- -
- Canonical SPDI
- NC_000001.11:197427614:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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 | ||
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HI score
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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. |
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CRB1 | - | - |
GRCh38 GRCh37 |
1911 | 1935 |
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. |
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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000006086.9 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV000086317.29 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2017 | RCV000656137.4 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 1, 2021 | RCV000787577.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV001052374.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 12, 2019 | RCV001074882.4 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 16, 2023 | RCV001250604.7 | |
CRB1-related maculopathy
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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2021 | RCV001352991.3 |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV003447471.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450615.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2021 | RCV002496279.3 | |
CRB1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV004540990.1 |
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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. |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 12
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001759998.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Likely pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950247.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Arg764Cys variant in CRB1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Arg764Cys variant in CRB1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, BP4, PP1-M, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa-deafness syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175772.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense variant c.2290C>T (p.Arg764Cys) in the CRB1 gene has been reported previously in a compound heterozygous and homozygous state in individuals affected with Autosomal … (more)
The missense variant c.2290C>T (p.Arg764Cys) in the CRB1 gene has been reported previously in a compound heterozygous and homozygous state in individuals affected with Autosomal recessive retinitis pigmentosa. Experimental studies have shown that this missense change affects protein function (den Hollander et al., 1999; Yang et al., 2016). This variant is reported with the allele frequency (0.007%) in the gnomAD and novel in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Arginine at position 764 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg764Cys in CRB1 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238130.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248712.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Oct 27, 2017)
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criteria provided, single submitter
Method: research
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Macular dystrophy
Affected status: yes
Allele origin:
germline
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Molecular Medicine, University of Leeds
Accession: SCV000611556.1
First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
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Pathogenic
(Aug 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240486.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446685.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: female
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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CRB1-related maculopathy
Affected status: yes
Allele origin:
germline
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548082.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Pathogenic
(Jul 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pigmented paravenous retinochoroidal atrophy
Retinitis pigmentosa 12 Leber congenital amaurosis 8
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810757.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001830805.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28129017, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28129017, 10508521, 20956273, 24512366, 26047050, 27670293, 28341475, 23379534, 29391521, 28559085, 31980526, 31630094, 31589614, 34884448, 31736247, 34426522, 33969091, 34946856, 33546218, 30718709, 32507488) (less)
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pigmented paravenous retinochoroidal atrophy
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004180028.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 8
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004180027.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 12
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004180029.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 8
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211120.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV001216583.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 764 of the CRB1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 764 of the CRB1 protein (p.Arg764Cys). This variant is present in population databases (rs62635654, gnomAD 0.01%). This missense change has been observed in individual(s) with CRB1-related retinopathy (PMID: 10508521, 11389483, 12700176, 20956273, 24512366, 26047050, 28129017, 28341475). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5732). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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CRB1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004774970.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CRB1 c.2290C>T variant is predicted to result in the amino acid substitution p.Arg764Cys. This variant has been documented to be causative for autosomal recessive … (more)
The CRB1 c.2290C>T variant is predicted to result in the amino acid substitution p.Arg764Cys. This variant has been documented to be causative for autosomal recessive retinitis pigmentosa (RP) and autosomal recessive Leber congenital amaurosis (den Hollander et al. 1999. PubMed ID: 10508521; Wang et al. 2015. PubMed ID: 26047050; Corton et al. 2013. PubMed ID: 23379534). (less)
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Pathogenic
(Oct 01, 1999)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 12
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026268.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 01, 2018 |
Comment on evidence:
For discussion of the arg764-to-cys (R764C) mutation in the CRB1 gene that was found in compound heterozygous state in a patient with retinitis pigmentosa-12 (RP12; … (more)
For discussion of the arg764-to-cys (R764C) mutation in the CRB1 gene that was found in compound heterozygous state in a patient with retinitis pigmentosa-12 (RP12; 600105) by den Hollander et al. (1999), see 604210.0003. The R764C mutation was also observed in compound heterozygous state with a ser430-to-ter (S430X) nonsense mutation. (less)
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Pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926557.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Dec 01, 2021)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis 8
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002583351.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis 8
Affected status: yes
Allele origin:
inherited
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Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001425472.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Number of individuals with the variant: 5
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958962.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966364.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000118463.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_CRB1:c.2290C>T
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
A clinical and molecular characterisation of CRB1-associated maculopathy. | Khan KN | European journal of human genetics : EJHG | 2018 | PMID: 29391521 |
Genotypic and Phenotypic Characteristics of CRB1-Associated Retinal Dystrophies: A Long-Term Follow-up Study. | Talib M | Ophthalmology | 2017 | PMID: 28341475 |
Retinal capillaritis in a CRB1-associated retinal dystrophy. | Murro V | Ophthalmic genetics | 2017 | PMID: 28129017 |
Comprehensive Molecular Diagnosis of a Large Chinese Leber Congenital Amaurosis Cohort. | Wang H | Investigative ophthalmology & visual science | 2015 | PMID: 26047050 |
Retinal Dystrophy with Intraretinal Cystoid Spaces Associated with Mutations in the Crumbs Homologue (CRB1) Gene. | Cordovez JA | Ophthalmic genetics | 2015 | PMID: 24512366 |
Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. | Henderson RH | The British journal of ophthalmology | 2011 | PMID: 20956273 |
Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. | Jacobson SG | Human molecular genetics | 2003 | PMID: 12700176 |
Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. | den Hollander AI | American journal of human genetics | 2001 | PMID: 11389483 |
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 rs62635654 ...
HelpRecord last updated May 27, 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.