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: 30212996, 30586318, 27004616, 28425981, 25557780, 27867342, 26925547, 33969091, 30996265, 33687977)
ClinVar Genomic variation as it relates to human health
NM_173689.7(CRB2):c.2400C>G (p.Asn800Lys)
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.
(6)
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.
Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(1)
Pathogenic(2); Uncertain significance(1)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_173689.7(CRB2):c.2400C>G (p.Asn800Lys)
Variation ID: 546072 Accession: VCV000546072.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q33.3 9: 123371542 (GRCh38) [ NCBI UCSC ] 9: 126133821 (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 Apr 15, 2024 Dec 15, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_173689.7:c.2400C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_775960.4:p.Asn800Lys missense NR_104603.2:n.1514C>G non-coding transcript variant NC_000009.12:g.123371542C>G NC_000009.11:g.126133821C>G NG_051311.1:g.22478C>G - Protein change
- N800K
- Other names
- -
- Canonical SPDI
- NC_000009.12:123371541:C:G
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00010
- 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 |
678 | 711 | |
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 (3) |
criteria provided, single submitter
|
Apr 5, 2022 | RCV000157660.8 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 15, 2023 | RCV000657852.12 |
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
(Sep 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000779609.6
First in ClinVar: Jul 09, 2018 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: 30212996, … (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: 30212996, 30586318, 27004616, 28425981, 25557780, 27867342, 26925547, 33969091, 30996265, 33687977) (less)
|
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Uncertain significance
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001543250.3
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 800 of the CRB2 protein (p.Asn800Lys). … (more)
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 800 of the CRB2 protein (p.Asn800Lys). This variant is present in population databases (rs765676223, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557780, 26925547, 27004616, 30586318). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 546072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CRB2 function (PMID: 36549870). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Apr 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ventriculomegaly-cystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002498611.2
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace asparagine with lysine at codon 800 of the CRB2 protein, p.(Asn800Lys). The asparagine residue is highly conserved (100 … (more)
This sequence change is predicted to replace asparagine with lysine at codon 800 of the CRB2 protein, p.(Asn800Lys). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is a glycosylation site N-linked (GlcNAc) asparagine in the laminin G-like 2 domain. There is a moderate physicochemical difference between asparagine and lysine. The variant is present in a large population cohort at a frequency of 0.02% (58/249,184 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.5% in the Ashkenazi Jewish sub-population. It has been identified with a second allele in at least five individuals with either or both ventriculomegaly (most common feature) and renal anomalies, and segregates with disease in multiple families (PMID: 25557780, 26925547, 27004616, 30996265). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PM2_Supporting, PP3. (less)
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809309.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
|
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Likely pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Ventriculomegaly with cystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142402.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_173689.5:c.2400C>G in the CRB2 gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in … (more)
NM_173689.5:c.2400C>G in the CRB2 gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in two siblings of a family affected with cerebral ventriculomegaly and renal microcysts, in trans with mutation c.2277G>A (p.Trp759Ter) and in another family in trans with mutation c.1928A>C (p.Glu643Ala) (PMID: 25557780). In-silico tools predict a damaging effect of the variant on protein function. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PP1; PP3. (less)
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Pathogenic
(Jan 08, 2015)
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no assertion criteria provided
Method: literature only
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VENTRICULOMEGALY WITH CYSTIC KIDNEY DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000207611.3
First in ClinVar: Feb 15, 2015 Last updated: Nov 19, 2022 |
Comment on evidence:
For discussion of the asn800-to-lys (N800K) mutation in the CRB2 gene that was found in compound heterozygous state with a W759X mutation in 2 sib … (more)
For discussion of the asn800-to-lys (N800K) mutation in the CRB2 gene that was found in compound heterozygous state with a W759X mutation in 2 sib fetuses with ventriculomegaly with cystic kidney disease (VMCKD; 219730) by Slavotinek et al. (2015), see 609720.0006. For discussion of the N800K mutation in the CRB2 gene that was found in compound heterozygous state with an E643A mutation in a fetus with VMCKD by Slavotinek et al. (2015), see 609720.0008. (less)
|
Comment:
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 800 of the CRB2 protein (p.Asn800Lys). This variant is present in population databases (rs765676223, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557780, 26925547, 27004616, 30586318). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 546072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CRB2 function (PMID: 36549870). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This sequence change is predicted to replace asparagine with lysine at codon 800 of the CRB2 protein, p.(Asn800Lys). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is a glycosylation site N-linked (GlcNAc) asparagine in the laminin G-like 2 domain. There is a moderate physicochemical difference between asparagine and lysine. The variant is present in a large population cohort at a frequency of 0.02% (58/249,184 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.5% in the Ashkenazi Jewish sub-population. It has been identified with a second allele in at least five individuals with either or both ventriculomegaly (most common feature) and renal anomalies, and segregates with disease in multiple families (PMID: 25557780, 26925547, 27004616, 30996265). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PM2_Supporting, PP3.
Comment:
NM_173689.5:c.2400C>G in the CRB2 gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in two siblings of a family affected with cerebral ventriculomegaly and renal microcysts, in trans with mutation c.2277G>A (p.Trp759Ter) and in another family in trans with mutation c.1928A>C (p.Glu643Ala) (PMID: 25557780). In-silico tools predict a damaging effect of the variant on protein function. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PP1; PP3.
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:
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: 30212996, 30586318, 27004616, 28425981, 25557780, 27867342, 26925547, 33969091, 30996265, 33687977)
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 800 of the CRB2 protein (p.Asn800Lys). This variant is present in population databases (rs765676223, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of CRB2-related conditions (PMID: 25557780, 26925547, 27004616, 30586318). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 546072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CRB2 function (PMID: 36549870). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This sequence change is predicted to replace asparagine with lysine at codon 800 of the CRB2 protein, p.(Asn800Lys). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is a glycosylation site N-linked (GlcNAc) asparagine in the laminin G-like 2 domain. There is a moderate physicochemical difference between asparagine and lysine. The variant is present in a large population cohort at a frequency of 0.02% (58/249,184 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.5% in the Ashkenazi Jewish sub-population. It has been identified with a second allele in at least five individuals with either or both ventriculomegaly (most common feature) and renal anomalies, and segregates with disease in multiple families (PMID: 25557780, 26925547, 27004616, 30996265). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PM2_Supporting, PP3.
Comment:
NM_173689.5:c.2400C>G in the CRB2 gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in two siblings of a family affected with cerebral ventriculomegaly and renal microcysts, in trans with mutation c.2277G>A (p.Trp759Ter) and in another family in trans with mutation c.1928A>C (p.Glu643Ala) (PMID: 25557780). In-silico tools predict a damaging effect of the variant on protein function. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PP1; PP3.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Loss of surface transport is a main cellular pathomechanism of CRB2 variants causing podocytopathies. | Möller-Kerutt A | Life science alliance | 2022 | PMID: 36549870 |
| Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus. | Date P | Scientific reports | 2019 | PMID: 30996265 |
| Diagnostic Utility of Exome Sequencing for Kidney Disease. | Groopman EE | The New England journal of medicine | 2019 | PMID: 30586318 |
| Expansion of phenotype and genotypic data in CRB2-related syndrome. | Lamont RE | European journal of human genetics : EJHG | 2016 | PMID: 27004616 |
| Expanding the phenotype of CRB2 mutations - A new ciliopathy syndrome? | Jaron R | Clinical genetics | 2016 | PMID: 26925547 |
| CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. | Slavotinek A | American journal of human genetics | 2015 | PMID: 25557780 |
Text-mined citations for rs765676223 ...
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 Sep 29, 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.