VCP
valosin containing protein, the group of AAA ATPases
Basic information
Region (hg38): 9:35053928-35072668
Links
Phenotypes
GenCC
Source:
- frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (Strong), mode of inheritance: AD
- amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
- inclusion body myopathy with Paget disease of bone and frontotemporal dementia (Supportive), mode of inheritance: AD
- frontotemporal dementia with motor neuron disease (Supportive), mode of inheritance: AD
- spastic paraplegia-Paget disease of bone syndrome (Supportive), mode of inheritance: AD
- adult-onset distal myopathy due to VCP mutation (Supportive), mode of inheritance: AD
- Charcot-Marie-Tooth disease type 2Y (Supportive), mode of inheritance: AD
- frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (Strong), mode of inheritance: AD
- Charcot-Marie-Tooth disease type 2Y (Strong), mode of inheritance: AD
- inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (Strong), mode of inheritance: AD
- inclusion body myopathy with Paget disease of bone and frontotemporal dementia (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Charcot-Marie-Tooth disease type, axonal type, 2Y; Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 | AD | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Neurologic | 7182974; 15034582; 16247064; 18260132; 18341608; 19704082; 19380227; 21145000; 21320982; 21984748; 22909335; 23152587; 25125609; 25878907 |
ClinVar
This is a list of variants' phenotypes submitted to
- Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (7 variants)
- not provided (5 variants)
- Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (4 variants)
- Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (3 variants)
- Frontotemporal dementia and/or amyotrophic lateral sclerosis 6;Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (2 variants)
- VCP-related disorder (1 variants)
- Global developmental delay (1 variants)
- Charcot-Marie-Tooth disease type 2Y (1 variants)
- Inborn genetic diseases (1 variants)
- INCLUSION BODY MYOPATHY WITHOUT EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1 (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the VCP gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 147 | 157 | ||||
| missense | 12 | 21 | 168 | 202 | ||
| nonsense | 2 | |||||
| start loss | 0 | |||||
| frameshift | 1 | |||||
| inframe indel | 3 | |||||
| splice donor/acceptor (+/-2bp) | 4 | |||||
| splice region | 14 | 37 | 5 | 56 | ||
| non coding | 18 | 93 | 25 | 136 | ||
| Total | 12 | 21 | 201 | 241 | 30 |
Variants in VCP
This is a list of pathogenic ClinVar variants found in the VCP region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-35056077-A-G | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Conflicting classifications of pathogenicity (Apr 01, 2023) | ||
| 9-35056081-G-GT | Amyotrophic Lateral Sclerosis, Dominant • Inclusion Body Myopathy, Dominant | Uncertain significance (Jun 14, 2016) | ||
| 9-35056116-G-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Benign/Likely benign (Jan 12, 2018) | ||
| 9-35056211-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Benign (Jan 13, 2018) | ||
| 9-35056232-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-35056329-C-T | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Uncertain significance (Jan 12, 2018) | ||
| 9-35056417-G-T | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Conflicting classifications of pathogenicity (Aug 01, 2022) | ||
| 9-35056521-G-A | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Benign (Jan 13, 2018) | ||
| 9-35056679-T-C | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Benign (Jan 12, 2018) | ||
| 9-35056732-TA-T | Inclusion Body Myopathy, Dominant • Amyotrophic Lateral Sclerosis, Dominant | Uncertain significance (Jun 14, 2016) | ||
| 9-35056735-G-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-35056750-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-35056770-G-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-35056900-C-A | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Uncertain significance (Jan 13, 2018) | ||
| 9-35056901-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-35056933-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-35056945-G-C | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Uncertain significance (Jan 13, 2018) | ||
| 9-35056964-C-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Benign (Jul 06, 2018) | ||
| 9-35057053-G-A | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Uncertain significance (Jan 13, 2018) | ||
| 9-35057054-C-T | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Uncertain significance (Jun 01, 2024) | ||
| 9-35057102-G-A | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Benign/Likely benign (Jan 12, 2018) | ||
| 9-35057105-G-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 | Benign/Likely benign (Jan 13, 2018) | ||
| 9-35057113-C-A | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • not specified • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 • Intellectual disability | Conflicting classifications of pathogenicity (Jul 01, 2024) | ||
| 9-35057118-T-C | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | Likely benign (May 11, 2023) | ||
| 9-35057126-C-T | Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 • Inborn genetic diseases | Likely benign (Feb 24, 2022) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| VCP | protein_coding | protein_coding | ENST00000358901 | 17 | 17186 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 0.00000760 | 125746 | 0 | 2 | 125748 | 0.00000795 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 5.41 | 126 | 448 | 0.281 | 0.0000291 | 5298 |
| Missense in Polyphen | 26 | 183.84 | 0.14143 | 2149 | ||
| Synonymous | -1.16 | 178 | 159 | 1.12 | 0.00000891 | 1623 |
| Loss of Function | 5.52 | 1 | 37.5 | 0.0267 | 0.00000248 | 438 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000289 | 0.0000289 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.00000879 | 0.00000879 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response (PubMed:29804830). Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites (PubMed:22020440, PubMed:22120668). Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage (PubMed:23042607, PubMed:23042605). Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995). Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy (PubMed:20104022, PubMed:27753622). Acts as a negative regulator of type I interferon production by interacting with DDX58/RIG-I: interaction takes place when DDX58/RIG-I is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of DDX58/RIG-I (PubMed:26471729). May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation (PubMed:21822278). May more particularly play a role in caveolins sorting in cells (PubMed:21822278, PubMed:23335559). By controlling the steady- state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333). {ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16186510, ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21118995, ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22020440, ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22607976, ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, ECO:0000269|PubMed:23335559, ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:26565908, ECO:0000269|PubMed:26692333, ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:29804830}.;
- Disease
- DISEASE: Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance. {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, ECO:0000269|PubMed:16247064, ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:17935506, ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, ECO:0000269|PubMed:27209344, ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:29804830}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia (ALS14) [MIM:613954]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia. {ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2Y (CMT2Y) [MIM:616687]: An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Legionellosis - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human);Disorders of transmembrane transporters;DNA Repair;Neutrophil degranulation;Disease;Signal Transduction;HSF1 activation;Defective CFTR causes cystic fibrosis;Cellular responses to stress;Josephin domain DUBs;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;Transport of small molecules;Hedgehog ligand biogenesis;Cellular responses to external stimuli;Signaling by Hedgehog;Asparagine N-linked glycosylation;ABC-family proteins mediated transport;Ovarian tumor domain proteases;Cellular response to heat stress;Deubiquitination;Translesion Synthesis by POLH;Protein ubiquitination;Protein methylation;Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template;DNA Damage Bypass;N-glycan trimming in the ER and Calnexin/Calreticulin cycle;Hh mutants that don,t undergo autocatalytic processing are degraded by ERAD;Hh mutants abrogate ligand secretion;ABC transporter disorders;Diseases of signal transduction;E3 ubiquitin ligases ubiquitinate target proteins
(Consensus)
Recessive Scores
- pRec
- 0.559
Intolerance Scores
- loftool
- rvis_EVS
- -0.34
- rvis_percentile_EVS
- 30.07
Haploinsufficiency Scores
- pHI
- hipred
- Y
- hipred_score
- 0.825
- ghis
- 0.636
Essentials
- essential_gene_CRISPR
- E
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.885
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Vcp
- Phenotype
- cellular phenotype; muscle phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span);
Zebrafish Information Network
- Gene name
- vcp
- Affected structure
- motor neuron
- Phenotype tag
- abnormal
- Phenotype quality
- truncated
Gene ontology
- Biological process
- DNA repair;double-strand break repair;protein folding;NADH metabolic process;endoplasmic reticulum to Golgi vesicle-mediated transport;autophagy;activation of cysteine-type endopeptidase activity involved in apoptotic process;cellular response to DNA damage stimulus;proteasomal protein catabolic process;positive regulation of mitochondrial membrane potential;macroautophagy;protein ubiquitination;protein deubiquitination;protein N-linked glycosylation via asparagine;viral genome replication;translesion synthesis;ubiquitin-dependent ERAD pathway;endoplasmic reticulum unfolded protein response;retrograde protein transport, ER to cytosol;positive regulation of protein complex assembly;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;endosome to lysosome transport via multivesicular body sorting pathway;protein hexamerization;cellular response to heat;stress granule disassembly;ERAD pathway;regulation of apoptotic process;proteasome-mediated ubiquitin-dependent protein catabolic process;neutrophil degranulation;establishment of protein localization;positive regulation of protein catabolic process;ATP metabolic process;regulation of synapse organization;mitotic spindle disassembly;protein homooligomerization;transmembrane transport;endoplasmic reticulum stress-induced pre-emptive quality control;aggresome assembly;error-free translesion synthesis;ER-associated misfolded protein catabolic process;flavin adenine dinucleotide catabolic process;positive regulation of canonical Wnt signaling pathway;autophagosome maturation;positive regulation of protein K63-linked deubiquitination;positive regulation of Lys63-specific deubiquitinase activity;regulation of aerobic respiration;cellular response to arsenite ion;positive regulation of oxidative phosphorylation;positive regulation of ubiquitin-specific protease activity;positive regulation of ATP biosynthetic process
- Cellular component
- proteasome complex;extracellular region;nucleus;nucleoplasm;cytoplasm;endoplasmic reticulum;endoplasmic reticulum membrane;lipid droplet;cytosol;cytoplasmic stress granule;protein-containing complex;VCP-NPL4-UFD1 AAA ATPase complex;secretory granule lumen;azurophil granule lumen;site of double-strand break;Derlin-1 retrotranslocation complex;myelin sheath;intracellular membrane-bounded organelle;perinuclear region of cytoplasm;extracellular exosome;glutamatergic synapse;ficolin-1-rich granule lumen;ATPase complex;VCP-NSFL1C complex
- Molecular function
- RNA binding;protein binding;ATP binding;lipid binding;ATPase activity;protein phosphatase binding;protein domain specific binding;polyubiquitin modification-dependent protein binding;ubiquitin protein ligase binding;deubiquitinase activator activity;K48-linked polyubiquitin modification-dependent protein binding;MHC class I protein binding;identical protein binding;ADP binding;ubiquitin-like protein ligase binding;BAT3 complex binding;ubiquitin-specific protease binding