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

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 24, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000824874.14

Allele description [Variation Report for NM_152564.5(VPS13B):c.1915C>T (p.Arg639Ter)]

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

Gene:

VPS13B:vacuolar protein sorting 13 homolog B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q22.2

Genomic location:

Preferred name:

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

HGVS:

NC_000008.11:g.99147912C>T
NG_007098.2:g.139647C>T
NM_015243.3:c.1915C>T
NM_017890.5:c.1915C>T
NM_152564.5:c.1915C>TMANE SELECT
NP_056058.2:p.Arg639Ter
NP_060360.3:p.Arg639Ter
NP_060360.3:p.Arg639Ter
NP_689777.3:p.Arg639Ter
NP_689777.3:p.Arg639Ter
LRG_351t1:c.1915C>T
LRG_351t2:c.1915C>T
LRG_351:g.139647C>T
LRG_351p1:p.Arg639Ter
LRG_351p2:p.Arg639Ter
NC_000008.10:g.100160140C>T
NM_017890.3:c.1915C>T
NM_017890.4:c.1915C>T
NM_152564.4:c.1915C>T

Protein change:

R639*

Links:

dbSNP: rs764776104

Molecular consequence:

NM_015243.3:c.1915C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_017890.5:c.1915C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_152564.5:c.1915C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Cohen syndrome (COH1)
Synonyms:: PEPPER SYNDROME; Cutis verticis gyrata, retinitis pigmentosa, and sensorineural deafness
Identifiers:: MONDO: MONDO:0008999; MedGen: C0265223; Orphanet: 193; OMIM: 216550

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000965781	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 4, 2016)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001132510	Counsyl	no assertion criteria provided	Likely pathogenic (Aug 20, 2015)	unknown	clinical testing
SCV001454810	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Apr 9, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002231527	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15141358, 16648375, 20461111, 28559085, 28492532
SCV005672009	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006076768	Center of Human Genetics, Hôpital Erasme	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2025)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Delineation of Cohen syndrome following a large-scale genotype-phenotype screen.

Kolehmainen J, Wilkinson R, Lehesjoki AE, Chandler K, Kivitie-Kallio S, Clayton-Smith J, Träskelin AL, Waris L, Saarinen A, Khan J, Gross-Tsur V, Traboulsi EI, Warburg M, Fryns JP, Norio R, Black GC, Manson FD.

Am J Hum Genet. 2004 Jul;75(1):122-7. Epub 2004 May 12.

PubMed [citation]

PMID:: 15141358
PMCID:: PMC1181995

Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome.

Seifert W, Holder-Espinasse M, Spranger S, Hoeltzenbein M, Rossier E, Dollfus H, Lacombe D, Verloes A, Chrzanowska KH, Maegawa GH, Chitayat D, Kotzot D, Huhle D, Meinecke P, Albrecht B, Mathijssen I, Leheup B, Raile K, Hennies HC, Horn D.

J Med Genet. 2006 May;43(5):e22.

PubMed [citation]

PMID:: 16648375
PMCID:: PMC2564527

See all PubMed Citations (6)

Details of each submission

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000965781.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV001132510.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001454810.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.1915C>T variant in VPS13B is a nonsense variant predicted to introduce a stop codon at amino acid 639. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 28559085). Given the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002231527.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV005672009.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center of Human Genetics, Hôpital Erasme, SCV006076768.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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