NM_152564.5(VPS13B):c.11832dup (p.Ser3945fs) AND Cohen syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 24, 2023
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:: RCV000050057.5

Allele description [Variation Report for NM_152564.5(VPS13B):c.11832dup (p.Ser3945fs)]

NM_152564.5(VPS13B):c.11832dup (p.Ser3945fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

8q22.2

Genomic location:

Preferred name:

NM_152564.5(VPS13B):c.11832dup (p.Ser3945fs)

HGVS:

NC_000008.11:g.99875504dup
NG_007098.2:g.867239dup
NM_017890.5:c.11907dup
NM_152564.5:c.11832dupMANE SELECT
NP_060360.3:p.Ser3970fs
NP_689777.3:p.Ser3945fs
LRG_351t1:c.11907_11908insC
LRG_351:g.867239dup
NC_000008.10:g.100887727_100887728insC
NC_000008.10:g.100887732dup
NM_017890.3:c.11907dupC
NM_017890.4:c.11907_11908insC
NM_017890.4:c.11907dupC
p.Ser3970GlnfsX22

Protein change:

S3945fs

Links:

dbSNP: rs180177374

NCBI 1000 Genomes Browser:

rs180177374

Molecular consequence:

NM_017890.5:c.11907dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_152564.5:c.11832dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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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S41 family peptidase [Caldicellulosiruptor naganoensis]
S41 family peptidase [Caldicellulosiruptor naganoensis]
gi|2414069177|gnl|extdb|OTJ99_00091 WAM32376.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082466	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (2) [See all records that cite these PMIDs] 15141358, 16648375
SCV000996441	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 25, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15141358, 25741868
SCV003513532	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15141358, 16648375, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000082466

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

no assertion criteria provided

probable-pathogenic

not provided

PubMed (2)
[See all records that cite these PMIDs]

SCV000996441

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 25, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003513532

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 24, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082466

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082466.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (2)

Description

Converted during submission to Likely pathogenic.

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

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000996441.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003513532.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 56644). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Lys3991Leufs*23) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15141358, 16648375). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs749120462, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ser3970Glnfs*22) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the VPS13B protein.

#	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

Last Updated: Sep 29, 2024

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