Human Gene Module / Chromosome 9 / VCP

VCPvalosin containing protein

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
17 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9p13.3
Associated Disorders
-
Relevance to Autism

Mah-som et al., 2023 identified 13 unrelated individuals harboring heterozygous variants in the VCP gene associated with a childhood-onset order characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly; three of the individuals in this study were formally diagnosed with autism (one of whom was enrolled in the SPARK study), while several additional individuals presented with autistic features and/or motor stereotypy. Furthermore, all disease-associated VCP missense and in-frame deletion variants reported in Mah-som et al., 2023 were experimentally shown to cause either a statistically significant increase or decrease in ATPase function compared to wild-type VCP, consistent with a gain-of-function or loss-of-function effect, respectively. A de novo loss-of-function variant and additional de novo missense variants in the VCP gene had previously been reported in ASD probands from the Simons Simplex Collection, the SPARK cohort, and the Autism Simplex Collection (O'Roak et al., 2014; Trost et al., 2022). Huang et al., 2020 observed that knock-in mice with a p.Arg95Gly mutation, which was originally identiifed in patients with IBMPFD and had been found to reduce the protein synthesis efficiency of neurons, displayed social deficits and reduced vocal communications.

Molecular Function

This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to VCP (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk O'Roak BJ , et al. (2014) Yes -
2 Support - Chrisovalantis Papadopoulos et al. (2017) No -
3 Support - Tzyy-Nan Huang et al. (2020) Yes -
4 Support - Trost B et al. (2022) Yes -
5 Primary - Annelise Y Mah-Som et al. (2023) No ASD or autistic features, ADHD, epilepsy/seizures,
6 Support - Noor Smal et al. () Yes -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.250A>G p.Met84Val missense_variant De novo - - 36368308 Trost B et al. (2022)
c.709-2A>G - splice_site_variant De novo - - 37883978 Annelise Y Mah-Som et al. (2023)
c.801_803del p.Phe267del inframe_deletion De novo - Simplex 38965372 Noor Smal et al. ()
c.1153A>C p.Thr385Pro missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.766C>G p.Arg256Gly missense_variant De novo - - 37883978 Annelise Y Mah-Som et al. (2023)
c.1084C>T p.Arg362Cys missense_variant De novo - - 37883978 Annelise Y Mah-Som et al. (2023)
c.1874G>C p.Arg625Pro missense_variant De novo - - 37883978 Annelise Y Mah-Som et al. (2023)
c.265del p.Arg89GlyfsTer8 frameshift_variant De novo - - 37883978 Annelise Y Mah-Som et al. (2023)
c.753G>T p.Lys251Asn missense_variant De novo - Simplex 37883978 Annelise Y Mah-Som et al. (2023)
c.812G>A p.Gly271Asp missense_variant De novo - Simplex 37883978 Annelise Y Mah-Som et al. (2023)
c.892C>T p.Pro298Ser missense_variant De novo - Simplex 37883978 Annelise Y Mah-Som et al. (2023)
c.1622C>A p.Ser541Tyr missense_variant De novo - Simplex 37883978 Annelise Y Mah-Som et al. (2023)
c.685C>T p.Leu229Phe missense_variant De novo - Multiplex 37883978 Annelise Y Mah-Som et al. (2023)
c.2257C>T p.Arg753Trp missense_variant Familial Paternal - 37883978 Annelise Y Mah-Som et al. (2023)
c.801_803del p.Phe267del inframe_deletion De novo - Simplex 37883978 Annelise Y Mah-Som et al. (2023)
c.901_903del p.Ile301del inframe_deletion De novo - Simplex 37883978 Annelise Y Mah-Som et al. (2023)
c.1545_1549del p.Phe516TrpfsTer16 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

1/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49347712647192

Ranking 4121/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999204738869

Ranking 434/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.867

Ranking 178/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.49187662515197

Ranking 431/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.090104316813816

Ranking 6332/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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