VPS13B

protein-coding

vacuolar protein sorting 13 homolog B, the group of bridge-like lipid transfer protein family

Gene summary

This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

CHS1
COH1

MANE transcript

NM_152564.5

Inheritance

ClinVar variants

P:1033U:2319B:1910

Top phenotype

Cohen syndrome

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr8:99,013,266-99,877,580

External References & Databases

Ensembl (ENSG00000132549)

Transcript & Mutation Effects

hg38 • Region Span ~864.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Cohen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: G2P

Cohen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: ClinGen

*VPS13B* was first reported in relation to autosomal recessive Cohen syndrome in 2003 (Kolehmainen et al., PMID: 12730828). More than 150 variants in *VPS13B*, mostly nonsense and frameshift, but also large deletions and missense variants, have been reported. Cohen syndrome is characterized by developmental delay, intellectual disability, typical facial gestalt, pigmentary retinopathy and intermittent neutropenia. It is over-represented in the Finnish population, likely due to a founder effect, with patients exhibiting a homogeneous phenotype. Eight variants (frameshift, nonsense and missense) that have been reported in nine probands in six publications (PMIDs: 12730828, 15173253, 19006247, 26104215, 29149870, 29758347) are included in this curation. Variants in this gene segregated with disease in 41 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is biallelic loss of function, with the majority of variants observed being null variants (frameshift and nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 21865173). Experimental evidence elucidating VPS13B protein function is still emerging. This gene-disease relationship is supported by studies showing that *Vps13b* knockdown in primary rat hippocampal neurons reduces neurite length (PMID: 25492866). VPS13B localizes to the Golgi apparatus, where it interacts with Golgi-associated proteins and is involved in Golgi assembly and glycosylation of other proteins (PMID: 24334764). In summary, there is definitive evidence supporting the relationship between *VPS13B* and autosomal recessive Cohen syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2018 (SOP Version 6).

Cohen syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: Orphanet

Cohen syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: Genomics England PanelApp

Cohen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: Natera

Cohen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: Myriad Women's Health

Cohen syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: Labcorp Genetics (formerly Invitae)

Cohen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Cohen syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008999

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cohen syndromeAR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious

Rationale: Though the condition may be frequently recognizable, individuals can have recurrent infections, and antiinfectious prophlyaxis and treatment (including G-CSF for neutropenia), as well as early and aggressive treatment of infections may be beneficial

Comments: The condition may be frequently recognizable due to characteristic features, including dysmorphisms

Refs: 4717588; 671157; 7438489; 7246618; 7166592; 6705238; 3989828; 3656371; 3223494; 9266925; 10466416; 10964838; 12676892; 12730828; 15211651; 15025727; 15141358; 20683995; 20301655; 20921020; 24311531

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS13B variants in ClinVar

40 Conditions Cataloged

Cohen syndromeTotal: 5797

VPS13B-related disorderTotal: 955

Inborn genetic diseasesTotal: 812

not providedTotal: 712

not specifiedTotal: 238

Intellectual disabilityTotal: 15

MicrocephalyTotal: 6

Retinitis pigmentosaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152564.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar	4 clinvar	52 clinvar	1760 clinvar	7 clinvar	1825
missense	5 clinvar	28 clinvar	2221 clinvar	123 clinvar	4 clinvar	2381
nonsense	163 clinvar	144 clinvar	6 clinvar			313
start loss		1 clinvar	1 clinvar			2
frameshift	285 clinvar	221 clinvar	18 clinvar		1 clinvar	525
splice donor/acceptor (+/-2bp)	33 clinvar	147 clinvar	21 clinvar	14 clinvar	1 clinvar	216
Total	488	545	2319	1897	13	5262

Highest pathogenic variant AF is 0.0044274074

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152564.5	RefSeq	NP_689777.3	61	MANE Select
ENST00000357162.7	Ensembl	ENSP00000349685.2	61	MANE Select
NM_015243.3	RefSeq	NP_056058.2	17	Standard
NM_017890.5	RefSeq	NP_060360.3	61	MANE Plus Clinical

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein transport

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358544
Coding exons: 61
Length: 864315
Individuals with no LoFs: 125352
Homozygous LoFs: 0
Heterozygous LoFs: 396
Defined: 125748
p: 0.00158

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.982	1947	2.07e+3	0.939	0.000107	26435
Missense (PolyPhen)		340	406.8	0.83579		4958
Synonymous	-0.626	772	750	1.03	0.0000396	7801
Loss of Function	5.71	105	190	0.553	0.00000994	2298

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.00087	0.00087	rare
Ashkenazi Jewish	0.0018	0.0018	notable
East Asian	0.0016	0.0016	notable
Finnish	0.0035	0.0035	notable
European (Non-Finnish)	0.0015	0.0015	notable
South Asian	0.0015	0.0014	notable
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in protein sorting in post Golgi membrane traffic. {ECO:0000250}.;

Recessive Scores

pRec: 0.176

Intolerance Scores

LoFtool: 0.933
RVIS EVS: -0.61
RVIS percentile EVS: 17.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.349

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High