This frameshifting variant in exon 10 of 13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in individuals with cerebral ventriculomegaly and nephrosis (PMID: 26925547, 27004616, 25557779). The c.3089_3104dup (p.Gly1036AlafsTer43) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.09% (28/30574) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.3089_3104dup (p.Gly1036AlafsTer43) variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_173689.7(CRB2):c.3089_3104dup (p.Gly1036fs)
Germline
Classification
Help
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.
(12)
Help
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
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_173689.7(CRB2):c.3089_3104dup (p.Gly1036fs)
Variation ID: 180701 Accession: VCV000180701.25
- Type and length
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Duplication, 16 bp
- Location
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Cytogenetic: 9q33.3 9: 123373608-123373609 (GRCh38) [ NCBI UCSC ] 9: 126135887-126135888 (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 15, 2015 Sep 29, 2024 May 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_173689.7:c.3089_3104dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_775960.4:p.Gly1036fs frameshift NM_173689.6:c.3089_3104dupGGCCCGGCGCGGCCCC NR_104603.2:n.2203_2218dup non-coding transcript variant NC_000009.12:g.123373620_123373635dup NC_000009.11:g.126135899_126135914dup NG_051311.1:g.24556_24571dup - Protein change
- G1036fs
- Other names
- -
- Canonical SPDI
- NC_000009.12:123373608:GGCGCGGCCCCGGCCCGGCGCGGCCCC:GGCGCGGCCCCGGCCCGGCGCGGCCCCGGCCCGGCGCGGCCCC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
- Links
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. |
|||
| CRB2 | - | - |
GRCh38 GRCh37 |
676 | 709 | |
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
|
Jan 8, 2015 | RCV000157656.3 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
May 29, 2024 | RCV000481736.22 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001003816.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 17, 2022 | RCV002498784.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 5, 2021 | RCV002516369.2 | |
|
CRB2-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV003335141.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000857358.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Sex: mixed
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
CRB2-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046435.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshifting variant in exon 10 of 13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more)
This frameshifting variant in exon 10 of 13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in individuals with cerebral ventriculomegaly and nephrosis (PMID: 26925547, 27004616, 25557779). The c.3089_3104dup (p.Gly1036AlafsTer43) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.09% (28/30574) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.3089_3104dup (p.Gly1036AlafsTer43) variant is classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(Jan 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ventriculomegaly-cystic kidney disease
Focal segmental glomerulosclerosis 9
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002804612.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001583169.2
First in ClinVar: May 10, 2021 Last updated: Mar 26, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly1036Alafs*43) in the CRB2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gly1036Alafs*43) in the CRB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB2 are known to be pathogenic (PMID: 27942854, 30212996). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557779, 27004616). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180701). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(May 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568837.9
First in ClinVar: Apr 27, 2017 Last updated: Sep 29, 2024 |
Comment:
Frame-shift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frame-shift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34670123, 32581362, 26925547, 31294511, 25557779, 27004616, 36071576, 36803301) (less)
|
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Pathogenic
(Apr 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019732.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003701141.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.3089_3104dup16 (p.G1036Afs*43) alteration, located in exon 10 (coding exon 10) of the CRB2 gene, consists of a duplication of GGCCCGGCGCGGCCCC at position 3089, causing … (more)
The c.3089_3104dup16 (p.G1036Afs*43) alteration, located in exon 10 (coding exon 10) of the CRB2 gene, consists of a duplication of GGCCCGGCGCGGCCCC at position 3089, causing a translational frameshift with a predicted alternate stop codon after 43 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported as compound heterozygous with CRB2 missense variants in two individuals with CRB2-related disease (Ebarasi, 2015; Lamont, 2016). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
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Pathogenic
(Jan 08, 2015)
|
no assertion criteria provided
Method: literature only
|
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 9
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000207607.1
First in ClinVar: Feb 15, 2015 Last updated: Feb 15, 2015 |
Comment on evidence:
For discussion of the 16-bp duplication in the CRB2 gene (c.3089_3104dup) that was found in compound heterozygous state in a patient with focal segmental glomerulosclerosis-9 … (more)
For discussion of the 16-bp duplication in the CRB2 gene (c.3089_3104dup) that was found in compound heterozygous state in a patient with focal segmental glomerulosclerosis-9 (FSGS9; 616220) by Ebarasi et al. (2015), see 609720.0002. (less)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Steroid-resistant nephrotic syndrome
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162267.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798304.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807418.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978119.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gly1036Alafs*43) in the CRB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB2 are known to be pathogenic (PMID: 27942854, 30212996). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557779, 27004616). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180701). For these reasons, this variant has been classified as Pathogenic.
Comment:
Frame-shift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34670123, 32581362, 26925547, 31294511, 25557779, 27004616, 36071576, 36803301)
Comment:
The c.3089_3104dup16 (p.G1036Afs*43) alteration, located in exon 10 (coding exon 10) of the CRB2 gene, consists of a duplication of GGCCCGGCGCGGCCCC at position 3089, causing a translational frameshift with a predicted alternate stop codon after 43 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported as compound heterozygous with CRB2 missense variants in two individuals with CRB2-related disease (Ebarasi, 2015; Lamont, 2016). Based on the available evidence, this alteration is 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:
This frameshifting variant in exon 10 of 13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in individuals with cerebral ventriculomegaly and nephrosis (PMID: 26925547, 27004616, 25557779). The c.3089_3104dup (p.Gly1036AlafsTer43) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.09% (28/30574) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.3089_3104dup (p.Gly1036AlafsTer43) variant is classified as Likely Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Gly1036Alafs*43) in the CRB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB2 are known to be pathogenic (PMID: 27942854, 30212996). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557779, 27004616). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180701). For these reasons, this variant has been classified as Pathogenic.
Comment:
Frame-shift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34670123, 32581362, 26925547, 31294511, 25557779, 27004616, 36071576, 36803301)
Comment:
The c.3089_3104dup16 (p.G1036Afs*43) alteration, located in exon 10 (coding exon 10) of the CRB2 gene, consists of a duplication of GGCCCGGCGCGGCCCC at position 3089, causing a translational frameshift with a predicted alternate stop codon after 43 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported as compound heterozygous with CRB2 missense variants in two individuals with CRB2-related disease (Ebarasi, 2015; Lamont, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| A case report of CRB2 mutation identified in a Chinese boy with focal segmental glomerulosclerosis. | Fan J | Medicine | 2018 | PMID: 30212996 |
| Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. | Udagawa T | Pediatric nephrology (Berlin, Germany) | 2017 | PMID: 27942854 |
| Expansion of phenotype and genotypic data in CRB2-related syndrome. | Lamont RE | European journal of human genetics : EJHG | 2016 | PMID: 27004616 |
| Defects of CRB2 cause steroid-resistant nephrotic syndrome. | Ebarasi L | American journal of human genetics | 2015 | PMID: 25557779 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRB2 | - | - | - | - |
Text-mined citations for rs879255251 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.