NM_152564.5(VPS13B):c.11831_11840del (p.Pro3944fs) AND Cohen syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV000050056.8

Allele description [Variation Report for NM_152564.5(VPS13B):c.11831_11840del (p.Pro3944fs)]

NM_152564.5(VPS13B):c.11831_11840del (p.Pro3944fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

8q22.2

Genomic location:

Preferred name:

NM_152564.5(VPS13B):c.11831_11840del (p.Pro3944fs)

HGVS:

NC_000008.11:g.99875503_99875512del
NG_007098.2:g.867238_867247del
NM_017890.5:c.11906_11915del
NM_152564.5:c.11831_11840delMANE SELECT
NP_060360.3:p.Pro3969fs
NP_060360.3:p.Pro3969fs
NP_689777.3:p.Pro3944fs
LRG_351t1:c.11906_11915del
LRG_351:g.867238_867247del
LRG_351p1:p.Pro3969fs
NC_000008.10:g.100887730_100887739del
NC_000008.10:g.100887731_100887740del
NM_017890.3:c.11906_11915del10
NM_017890.4:c.11906_11915del
NM_017890.4:c.11906_11915del10
NM_017890.4:c.11906_11915delCCAGCTGTTC

Protein change:

P3944fs

Links:

dbSNP: rs386834069

NCBI 1000 Genomes Browser:

rs386834069

Molecular consequence:

NM_017890.5:c.11906_11915del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_152564.5:c.11831_11840del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000082465	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV000699444	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 25, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19006247, 15141358, 29431110 Citation Link,
SCV001583216	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	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

SCV000082465

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

no assertion criteria provided

probable-pathogenic

not provided

PubMed (1)
[See all records that cite this PMID]

SCV000699444

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 25, 2022)

germline

clinical testing

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

Citation Link,

SCV001583216

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

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: SCV000082465

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	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Expanded mutational spectrum in Cohen syndrome, tissue expression, and transcript variants of COH1.

Seifert W, Holder-Espinasse M, Kühnisch J, Kahrizi K, Tzschach A, Garshasbi M, Najmabadi H, Walter Kuss A, Kress W, Laureys G, Loeys B, Brilstra E, Mancini GM, Dollfus H, Dahan K, Apse K, Hennies HC, Horn D.

Hum Mutat. 2009 Feb;30(2):E404-20. doi: 10.1002/humu.20886.

PubMed [citation]

PMID:: 19006247

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

Reuter MS, Walker S, Thiruvahindrapuram B, Whitney J, Cohn I, Sondheimer N, Yuen RKC, Trost B, Paton TA, Pereira SL, Herbrick JA, Wintle RF, Merico D, Howe J, MacDonald JR, Lu C, Nalpathamkalam T, Sung WWL, Wang Z, Patel RV, Pellecchia G, Wei J, et al.

CMAJ. 2018 Feb 5;190(5):E126-E136. doi: 10.1503/cmaj.171151.

PubMed [citation]

PMID:: 29431110
PMCID:: PMC5798982

See all PubMed Citations (5)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082465.1

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

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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699444.4

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

Description

Variant summary: VPS13B c.11906_11915del10 (p.Pro3969LeufsX41) 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. The variant was absent in 251604 control chromosomes (gnomAD). c.11906_11915del10 has been reported in the literature in at-least one compound heterozygous individual affected with Cohen Syndrome (Kolehmainen_2004) and subsequently cited by others (example Seifert_2009, Reuter_2018). These data do not allow firm conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely 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, SCV001583216.4

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

Description

This sequence change creates a premature translational stop signal (p.Pro3969Leufs*41) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the VPS13B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 15141358; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56643). This variant disrupts the C-terminus of the VPS13B protein. Other variant(s) that disrupt this region (p.Ser3970Glnfs*22) have been observed in individuals with VPS13B-related conditions (PMID: 16648375). This suggests that this may be a clinically significant region of the protein. 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

Last Updated: Sep 29, 2024

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