ClinVar Genomic variation as it relates to human health
NM_152564.5(VPS13B):c.3427C>T (p.Arg1143Ter)
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_152564.5(VPS13B):c.3427C>T (p.Arg1143Ter)
Variation ID: 56658 Accession: VCV000056658.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q22.2 8: 99442617 (GRCh38) [ NCBI UCSC ] 8: 100454845 (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 Jul 24, 2013 Oct 8, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152564.5:c.3427C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689777.3:p.Arg1143Ter nonsense NM_017890.5:c.3427C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060360.3:p.Arg1143Ter nonsense NM_152564.4:c.3427C>T NC_000008.11:g.99442617C>T NC_000008.10:g.100454845C>T NG_007098.2:g.434352C>T LRG_351:g.434352C>T LRG_351t1:c.3427C>T LRG_351p1:p.Arg1143Ter - Protein change
- R1143*
- Other names
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- Canonical SPDI
- NC_000008.11:99442616: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
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
- 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 | ||
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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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VPS13B | - | - |
GRCh38 GRCh37 |
5958 | 6028 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000050071.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 6, 2020 | RCV000422497.3 | |
VPS13B-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Mar 26, 2024 | RCV004742240.1 |
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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Pathogenic
(Jan 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cohen syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338009.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: VPS13B c.3427C>T (p.Arg1143X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: VPS13B c.3427C>T (p.Arg1143X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-05 in 251098 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (4e-05 vs 0.0025), allowing no conclusion about variant significance. c.3427C>T has been reported in the literature in individuals affected with Cohen Syndrome (Katzaki_2007, El Chehadeh-Djebbar_2010). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Cohen syndrome
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005052000.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Nov 06, 2020)
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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: SCV000520846.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense 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; This variant is associated with the following publications: (PMID: 30843084, 32919079, 25525159, 24334764, 20656880, 17990063, 20461111, 31980526, 31589614) (less)
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Pathogenic
(May 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cohen syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809093.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cohen syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000949743.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1143*) in the VPS13B gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1143*) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs386834080, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with VPS13B-related disease (PMID: 17990063, 19006247, 20461111, 20656880). ClinVar contains an entry for this variant (Variation ID: 56658). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Cohen syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804746.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Cohen syndrome
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082480.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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Likely pathogenic
(Mar 17, 2015)
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no assertion criteria provided
Method: clinical testing
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Cohen syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132507.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Mar 26, 2024)
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no assertion criteria provided
Method: clinical testing
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VPS13B-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005361158.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The VPS13B c.3427C>T variant is predicted to result in premature protein termination (p.Arg1143*). This variant was reported in individuals with Cohen syndrome (Katzaki et al … (more)
The VPS13B c.3427C>T variant is predicted to result in premature protein termination (p.Arg1143*). This variant was reported in individuals with Cohen syndrome (Katzaki et al 2007. PubMed ID: 17990063; Duplomb L et al 2013. PubMed ID: 24334764; Parri V et al 2010. PubMed ID: 20461111). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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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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Cohen syndrome is associated with major glycosylation defects. | Duplomb L | Human molecular genetics | 2014 | PMID: 24334764 |
Changing facial phenotype in Cohen syndrome: towards clues for an earlier diagnosis. | El Chehadeh-Djebbar S | European journal of human genetics : EJHG | 2013 | PMID: 23188044 |
The power of high-resolution non-targeted array-CGH in identifying intragenic rearrangements responsible for Cohen syndrome. | El Chehadeh-Djebbar S | Journal of medical genetics | 2011 | PMID: 21330571 |
Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome. | El Chehadeh S | Journal of medical genetics | 2010 | PMID: 20656880 |
High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome. | Parri V | European journal of human genetics : EJHG | 2010 | PMID: 20461111 |
Expanded mutational spectrum in Cohen syndrome, tissue expression, and transcript variants of COH1. | Seifert W | Human mutation | 2009 | PMID: 19006247 |
Clinical and molecular characterization of Italian patients affected by Cohen syndrome. | Katzaki E | Journal of human genetics | 2007 | PMID: 17990063 |
Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. | Seifert W | Journal of medical genetics | 2006 | PMID: 16648375 |
Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. | Kolehmainen J | American journal of human genetics | 2004 | PMID: 15141358 |
Text-mined citations for rs386834080 ...
HelpRecord last updated Oct 13, 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.