VCV000265334.16 - ClinVar

NM_152564.5(VPS13B):c.1915C>T (p.Arg639Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

6 out of 8 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_152564.5(VPS13B):c.1915C>T (p.Arg639Ter)

Variation ID: 265334 Accession: VCV000265334.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.2 8: 99147912 (GRCh38) [ NCBI UCSC ] 8: 100160140 (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	Dec 6, 2016	May 15, 2025	Jan 24, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_152564.5:c.1915C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689777.3:p.Arg639Ter	nonsense
NM_017890.5:c.1915C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060360.3:p.Arg639Ter	nonsense
NM_015243.3:c.1915C>T	NP_056058.2:p.Arg639Ter	nonsense
NC_000008.11:g.99147912C>T
NC_000008.10:g.100160140C>T
NG_007098.2:g.139647C>T
LRG_351:g.139647C>T
LRG_351t1:c.1915C>T	LRG_351p1:p.Arg639Ter
LRG_351t2:c.1915C>T	LRG_351p2:p.Arg639Ter

... more HGVS ... less HGVS

Protein change

R639*

Other names

Canonical SPDI

NC_000008.11:99147911: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.

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

Links

ClinGen: CA4822777 dbSNP: rs764776104 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	6272	6342

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 6, 2024	RCV000255734.9
Cohen syndrome	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 24, 2025	RCV000824874.11

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 (Dec 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322116.8 First in ClinVar: Oct 10, 2016 Last updated: Dec 28, 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 … (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: 31589614, Beene_2015_Paper, 28559085) (less)

Pathogenic (Jan 24, 2025) C Contributing to aggregate classification	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: SCV002231527.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 15141358‚ 16648375‚ 20461111‚ 28559085 Comment: This sequence change creates a premature translational stop signal (p.Arg639) 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.Arg639) 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 (rs764776104, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 265334). For these reasons, this variant has been classified as Pathogenic. (less)

Likely pathogenic (Jan 04, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000965781.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019

Pathogenic (May 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005672009.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025

Pathogenic (Dec 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703985.3 First in ClinVar: Apr 02, 2018 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VPS13B Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed

Pathogenic (Jan 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: yes Allele origin: inherited	Center of Human Genetics, Hôpital Erasme Accession: SCV006076768.1 First in ClinVar: May 15, 2025 Last updated: May 15, 2025

Pathogenic (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001454810.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Likely pathogenic (Aug 20, 2015) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV001132510.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019

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: 31589614, Beene_2015_Paper, 28559085)

Comment:

This sequence change creates a premature translational stop signal (p.Arg639*) 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 (rs764776104, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 265334). For these reasons, this variant has been 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
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
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VPS13B	-	-	-	-

Text-mined citations for rs764776104 ...

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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_152564.5(VPS13B):c.1915C>T (p.Arg639Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs764776104 ...