VCV000002823.19 - ClinVar

NM_152564.5(VPS13B):c.2911C>T (p.Arg971Ter)

Germline

Classification

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.

(8)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_152564.5(VPS13B):c.2911C>T (p.Arg971Ter)

Variation ID: 2823 Accession: VCV000002823.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.2 8: 99384294 (GRCh38) [ NCBI UCSC ] 8: 100396522 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	May 5, 2016	Nov 24, 2024	May 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_152564.5:c.2911C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689777.3:p.Arg971Ter	nonsense
NM_017890.5:c.2911C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060360.3:p.Arg971Ter	nonsense
NC_000008.11:g.99384294C>T
NC_000008.10:g.100396522C>T
NG_007098.2:g.376029C>T
LRG_351:g.376029C>T
LRG_351t1:c.2911C>T	LRG_351p1:p.Arg971Ter

... more HGVS ... less HGVS

Protein change

R971*

Other names

Canonical SPDI

NC_000008.11:99384293:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA252438 OMIM: 607817.0006 dbSNP: rs120074152 VarSome

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
Gene	OMIM	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.
VPS13B		-	-	GRCh38 GRCh37	5964	6034

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.
Cohen syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV000002957.20
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 11, 2017	RCV000624804.2
not provided	Pathogenic (1)	criteria provided, single submitter	May 8, 2024	RCV004786234.1

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.
Pathogenic (Jan 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: yes Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000700150.1 First in ClinVar: Mar 23, 2018 Last updated: Mar 23, 2018	Sex: female
Pathogenic (Apr 09, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001572475.1 First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021	Publications: PubMed (4) PubMed: 19006247‚ 15154116‚ 30843084‚ 32384097 Comment: Variant summary: VPS13B c.2911C>T (p.Arg971X) 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.2911C>T (p.Arg971X) 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-06 in 251120 control chromosomes. c.2911C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Cohen Syndrome (e.g. Hennies_2004, Seifert_2008, Duplomb_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020872.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 11, 2017)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742912.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 15154116‚ 19006247 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Caucasian/German/Irish/Italian
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001390259.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 15141358‚ 16648375‚ 20461111‚ 15154116 Comment: This sequence change creates a premature translational stop signal (p.Arg971) 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.Arg971) 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 (rs120074152, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15154116). ClinVar contains an entry for this variant (Variation ID: 2823). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 08, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005401372.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: 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; Not … (more) 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30843084, 26104215, 22382802, 21418059, 35898454, 36368352, 15154116, 32384097) (less)
Pathogenic (Jul 01, 2004)	no assertion criteria provided Method: literature only	COHEN SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023115.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2018	Publications: PubMed (1) PubMed: 15154116 Comment on evidence: In a Turkish family with Cohen syndrome (COH1; 216550), Hennies et al. (2004) identified an arg971-to-ter (R971X) mutation resulting from a 2911C-T transition in exon … (more) In a Turkish family with Cohen syndrome (COH1; 216550), Hennies et al. (2004) identified an arg971-to-ter (R971X) mutation resulting from a 2911C-T transition in exon 20 of the COH1 gene. (less)
Pathogenic (Oct 12, 2021)	no assertion criteria provided Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002079537.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

Variant summary: VPS13B c.2911C>T (p.Arg971X) 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-06 in 251120 control chromosomes. c.2911C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Cohen Syndrome (e.g. Hennies_2004, Seifert_2008, Duplomb_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg971*) 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 (rs120074152, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15154116). ClinVar contains an entry for this variant (Variation ID: 2823). For these reasons, this variant has been classified as Pathogenic.

Comment:

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30843084, 26104215, 22382802, 21418059, 35898454, 36368352, 15154116, 32384097)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center.	Kleinendorst L	PloS one	2020	PMID: 32384097
Serpin B1 defect and increased apoptosis of neutrophils in Cohen syndrome neutropenia.	Duplomb L	Journal of molecular medicine (Berlin, Germany)	2019	PMID: 30843084
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
Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome.	Seifert W	Journal of medical genetics	2006	PMID: 16648375
Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome.	Hennies HC	American journal of human genetics	2004	PMID: 15154116
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 rs120074152 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_152564.5(VPS13B):c.2911C>T (p.Arg971Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs120074152 ...