NM_152564.5(VPS13B):c.8044C>T (p.Arg2682Ter) AND Cohen syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 5, 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:: RCV000050104.8

Allele description [Variation Report for NM_152564.5(VPS13B):c.8044C>T (p.Arg2682Ter)]

NM_152564.5(VPS13B):c.8044C>T (p.Arg2682Ter)

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.8044C>T (p.Arg2682Ter)

HGVS:

NC_000008.11:g.99809477C>T
NG_007098.2:g.801212C>T
NM_017890.5:c.8119C>T
NM_152564.5:c.8044C>TMANE SELECT
NP_060360.3:p.Arg2707Ter
NP_060360.3:p.Arg2707Ter
NP_689777.3:p.Arg2682Ter
LRG_351t1:c.8119C>T
LRG_351:g.801212C>T
LRG_351p1:p.Arg2707Ter
NC_000008.10:g.100821705C>T
NM_017890.4:c.8119C>T

Protein change:

R2682*

Links:

dbSNP: rs386834110

NCBI 1000 Genomes Browser:

rs386834110

Molecular consequence:

NM_017890.5:c.8119C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_152564.5:c.8044C>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

Recent activity

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WW domain binding protein VOPP1 isoform X3 [Rattus norvegicus]
WW domain binding protein VOPP1 isoform X3 [Rattus norvegicus]
gi|2678938516|ref|XP_063142345.1|

Protein
Ascomycota sp. AFTOL 1976 18S ribosomal RNA gene, partial sequence
Ascomycota sp. AFTOL 1976 18S ribosomal RNA gene, partial sequence
gi|667671250|gb|KJ766819.1|

Nucleotide
Ascomycota sp. AFTOL 1637 18S ribosomal RNA gene, partial sequence
Ascomycota sp. AFTOL 1637 18S ribosomal RNA gene, partial sequence
gi|667671251|gb|KJ766820.1|

Nucleotide
Micralestes lualabae isolate B2_44_8695_J201 cytochrome c oxidase subunit I (COI...
Micralestes lualabae isolate B2_44_8695_J201 cytochrome c oxidase subunit I (COI) gene, partial cds; mitochondrial
gi|1047412349|gb|KX186340.1|

Nucleotide
IQ domain-containing protein F5 [Mus musculus]
IQ domain-containing protein F5 [Mus musculus]
gi|222831630|ref|NP_083576.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082513	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]
SCV001360940	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 25, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19006247, 17990063 Citation Link,
SCV001586270	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15141358, 16648375, 20461111, 17990063, 28492532
SCV002809730	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082513

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

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 (7)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082513.1

#	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, SCV001360940.1

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

Description

Variant summary: VPS13B c.8119C>T (p.Arg2707X) 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 likely pathogenic/pathogenic by our laboratory (eg. c.8515C>T (p.Arg2839X), c.10156dupA (p.Thr3386fsX3), and c.10946G>A (p.Trp3649X)). The variant allele was found at a frequency of 4.1e-06 in 245828 control chromosomes (gnomAD). c.8119C>T has been reported in the literature in a compound heterozygote individual affected with Cohen Syndrome (Katzaki_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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, SCV001586270.4

#	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.Arg2707*) 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 (rs386834110, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 17990063). 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: 56691). 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, SCV002809730.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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