ClinVar Genomic variation as it relates to human health
NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del)
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.
Pathogenic(9); Likely pathogenic(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del)
Variation ID: 96659 Accession: VCV000096659.52
- Type and length
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Deletion, 9 bp
- Location
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Cytogenetic: 1q31.3 1: 197328844-197328852 (GRCh38) [ NCBI UCSC ] 1: 197297974-197297982 (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 Jun 28, 2015 May 12, 2024 Feb 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_201253.3:c.498_506del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_957705.1:p.Ile167_Gly169del inframe deletion NM_001193640.2:c.498_506del NP_001180569.1:p.Ile167_Gly169del inframe deletion NM_001257965.2:c.291_299del NP_001244894.1:p.Ile98_Gly100del inframe deletion NM_001257966.2:c.498_506del NP_001244895.1:p.Ile167_Gly169del inframe deletion NM_201253.2:c.498_506del9 NM_201253.2:c.498_506delAATTGATGG NR_047563.2:n.659_667del non-coding transcript variant NR_047564.2:n.659_667del non-coding transcript variant NC_000001.11:g.197328849_197328857del NC_000001.10:g.197297979_197297987del NG_008483.2:g.132388_132396del - Protein change
- Other names
- NC_000001.10:g.197297979_197297987del
- NP_957705.1:p.(Ile167_Gly169del)
- Canonical SPDI
- NC_000001.11:197328843:GATGGAATTGATGG:GATGG
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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
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The frequency of the allele represented by this VCV record.
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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 benign (1) |
criteria provided, single submitter
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Sep 25, 2013 | RCV000082822.8 | |
Pathogenic (3) |
criteria provided, single submitter
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Oct 27, 2017 | RCV000505172.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2017 | RCV000615750.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000798096.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000986483.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2018 | RCV001075317.3 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2022 | RCV000598962.25 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2021 | RCV001353031.2 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 28, 2023 | RCV001250581.3 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2024 | RCV004528300.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV003324504.3 | |
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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 benign
(Sep 25, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000114870.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 28, 2021)
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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: SCV000709902.3
First in ClinVar: Apr 02, 2018 Last updated: Mar 04, 2023 |
Comment:
In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27628848, 25474345, 17297689, 30609409, 31047384, 32511120, 23379534, 27096895, 28041643, 27258436, 28819299, 28181551, 29391521, 29555955, 29869924, 31879567, 33773389, 33029571, 32037395) (less)
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Pathogenic
(Oct 28, 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: SCV004211096.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 27, 2022)
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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: SCV003830169.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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: SCV000611552.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
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Pathogenic
(Aug 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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CRB1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914374.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CRB1 c.498_506delAATTGATGG (p.Ile167_Gly169del) variant is an inframe deletion that has been reported in at least five studies in which it is identified in a … (more)
The CRB1 c.498_506delAATTGATGG (p.Ile167_Gly169del) variant is an inframe deletion that has been reported in at least five studies in which it is identified in a total of 10 individuals, including in one in a homozygous state and in nine in a compound heterozygous state, and in three additional alleles (Corton et al. 2013; Zaneveld et al. 2015; Sergouniotis et al. 2016; Carss et al. 2017; Shah et al. 2017). Individuals with the variant present with a range of phenotypes including early-onset retinitis pigmentosa, Stargardt macular dystrophy, isolated maculopathy, macular dystrophy, and retinal dystrophy. No individuals with the variant have been reported with Leber congenital amaurosis or pigmented paravenous chorioretinal atrophy. Control data are unavailable for this variant, which is reported at a frequency of 0.00108 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Ile167_Gly169del variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Nov 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive bestrophinopathy
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731981.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Ile98_Gly100del (NM_001257965.1 c.291_299delAATTGATGG) variant in CRB1 (al so reported as NM_201253.2:p.Ile167_Gly169del) has been previously reported in 1 homozygous and 7 compound heterozygous individuals with … (more)
The p.Ile98_Gly100del (NM_001257965.1 c.291_299delAATTGATGG) variant in CRB1 (al so reported as NM_201253.2:p.Ile167_Gly169del) has been previously reported in 1 homozygous and 7 compound heterozygous individuals with retinal disorders inclu ding retinal dystrophy, retinitis pigmentosa, and familial foveal retinoschisis (Corton 2013, Vincent 2016, Riera 2017). It has also been identified in 0.1% (12 4/126,500) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs748136623). This variant is a deletion of 3 amino acids at position 98-100, and it is unclear if this deletion will imp act the protein. In summary, although additional studies are required to fully e stablish its clinical significance, the p.Ile98_Gly100del variant is likely path ogenic for retinal disorders based on its biallelic occurrence individuals with these diseases. ACMG/AMP Criteria applied: PM3 (upgraded to Strong based on mult iple occurrences), PM4 (Richards 2015). (less)
Number of individuals with the variant: 2
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Likely pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135495.1
First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020 |
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Pathogenic
(Feb 15, 2018)
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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: SCV001240935.1
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: SCV001447636.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: male
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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: SCV001548145.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: research
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Cone dystrophy
Affected status: yes
Allele origin:
germline
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Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030394.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Comment:
This variant was classified as Pathogenic based on ACMG criteria: PP5, PM2, PM4, PS4, PM1.
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Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 1
Sex: female
Geographic origin: Portugal
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Pathogenic
(Jan 31, 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: SCV000937693.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This variant, c.498_506del, results in the deletion of 3 amino acid(s) of the CRB1 protein (p.Ile167_Gly169del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.498_506del, results in the deletion of 3 amino acid(s) of the CRB1 protein (p.Ile167_Gly169del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748136623, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with retinal dystrophies (PMID: 23379534, 28181551; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 96659). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 09, 2024)
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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: SCV004726875.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CRB1 c.498_506del9 variant is predicted to result in an in-frame deletion (p.Ile167_Gly169del). This variant has been detected in the heterozygous, compound heterozygous, and homozygous … (more)
The CRB1 c.498_506del9 variant is predicted to result in an in-frame deletion (p.Ile167_Gly169del). This variant has been detected in the heterozygous, compound heterozygous, and homozygous states in patients with retinal disorders (Corton et al. 2013. PubMed ID: 23379534; Sergouniotis et al. 2016. PubMed ID: 27628848, Table S2; Zaneveld et al. 2015. PubMed ID: 25474345). This variant was found in all patients in a study of seven unrelated individuals who presented with macular dystrophy (Khan et al. 2018. PubMed ID: 29391521). The authors mentioned that this variant is the most prevalent disease-causing variant in non-Asian populations and may result in both mild and localized retinal dysfunction (Khan et al. 2018. PubMed ID: 29391521). This variant is reported with a global allele frequency of 0.062% in gnomAD including at least one homozygote, which is higher than expected for a fully-penetrant pathogenic variant. This variant has conflicting interpretations in ClinVar ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/96659/). At PreventionGenetics, we have observed this variant along with a protein truncating variant and in the absence of a second causative variant in several patients. Given the evidence, we interpret c.498_506del (p.Ile167_Gly169del) as likely pathogenic for autosomal recessive disease and uncertain for autosomal dominant disease. (less)
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Pathogenic
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246859.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
CRB1: PM3:Very Strong, PM2
Number of individuals with the variant: 5
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Likely pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Macular dystrophy
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598923.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
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Uncertain significance
(-)
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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: SCV001964681.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Macular dystrophy
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804629.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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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:
maternal
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Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001425448.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Number of individuals with the variant: 2
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Uncertain significance
(-)
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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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922980.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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 first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. | Peter VG | PNAS nexus | 2023 | PMID: 36909829 |
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
A clinical and molecular characterisation of CRB1-associated maculopathy. | Khan KN | European journal of human genetics : EJHG | 2018 | PMID: 29391521 |
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 |
Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies. | Riera M | Scientific reports | 2017 | PMID: 28181551 |
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 |
Isolated maculopathy associated with biallelic CRB1 mutations. | Shah N | Ophthalmic genetics | 2017 | PMID: 27096895 |
The role of small in-frame insertions/deletions in inherited eye disorders and how structural modelling can help estimate their pathogenicity. | Sergouniotis PI | Orphanet journal of rare diseases | 2016 | PMID: 27628848 |
Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis. | Vincent A | Investigative ophthalmology & visual science | 2016 | PMID: 27258436 |
Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions. | Zaneveld J | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25474345 |
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 |
Gene symbol: CRB1. Disease: Leber congenital amaurosis. Accession #Hd0510. | Vallespin E | Human genetics | 2006 | PMID: 17297678 |
Gene symbol: CRB1. Disease: early onset retinitis pigmentosa. | Vallespin E | Human genetics | 2006 | PMID: 17128490 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRB1 | - | - | - | - |
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Text-mined citations for rs398124615 ...
HelpRecord last updated May 12, 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.