Human Gene Module / Chromosome 8 / VPS13B

VPS13Bvacuolar protein sorting 13 homolog B (yeast)

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
10 / 20
Rare Variants / Common Variants
62 / 0
Aliases
VPS13B, CHS1,  COH1,  DKFZp313I0811,  KIAA0532
Associated Syndromes
Cohen syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
8q22.2
Associated Disorders
EPS, EP, ID, ASD, DD/NDD
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003).

Molecular Function

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.

Reports related to VPS13B (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and ... Kolehmainen J , et al. (2003) No ASD
2 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
3 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
4 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
5 Recent Recommendation Using whole-exome sequencing to identify inherited causes of autism. Yu TW , et al. (2013) Yes -
6 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut... Koshimizu E , et al. (2013) Yes ID, epilepsy
7 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. Cukier HN , et al. (2014) Yes -
8 Recent Recommendation Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite ou... Seifert W , et al. (2014) No -
9 Support Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism. Ionita-Laza I , et al. (2014) Yes -
10 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No DD
11 Support Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features. Rafiq MA , et al. (2015) No DD, ID, autistic features
12 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No Microcephaly
13 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
14 Support Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. Charng WL , et al. (2016) No -
15 Support Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Riazuddin S , et al. (2016) No -
16 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
17 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
18 Support Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications. Kalsner L , et al. (2017) Yes -
19 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No ASD
20 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
Rare Variants   (62)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.2889G>A p.Trp963Ter stop_gained Unknown - Simplex 23352163 Yu TW , et al. (2013)
c.7051C>T p.Arg2351Ter stop_gained Familial - Simplex 28831199 Li J , et al. (2017)
c.2825-8140_2825-8139insC - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.3058C>A p.Pro1020Thr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5033G>A p.Arg1678Gln missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.8185G>A p.Gly2729Arg missense_variant Unknown - Simplex 23352163 Yu TW , et al. (2013)
c.9984T>A p.Ser3328Arg missense_variant Unknown - Simplex 23352163 Yu TW , et al. (2013)
c.292-1G>A - splice_site_variant - Both parents Unknown 31130284 Monies D , et al. (2019)
c.10997G>C p.Ser3666Thr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.11426C>T p.Pro3809Leu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.11146G>A p.Ala3716Thr missense_variant Unknown - Simplex 23352163 Yu TW , et al. (2013)
c.9095G>A p.Trp3032Ter stop_gained Familial Paternal - 29271092 Kalsner L , et al. (2017)
- A1570GA1573Ter copy_number_loss Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.2074C>T p.Arg692Ter stop_gained Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.8472G>A p.Trp2824Ter stop_gained Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.820T>G p.Phe274Val missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
- - copy_number_loss Familial Both parents Multi-generational 26104215 Rafiq MA , et al. (2015)
c.2058G>A p.Arg686= synonymous_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.511G>A p.Val171Ile missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.4197T>C p.Gly1399= missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.11960C>G p.Pro3987Arg missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.1559A>G p.His520Arg missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.1832G>A p.Arg611Lys missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.6578T>G p.Leu2193Arg missense_variant Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.3361A>T p.Ile1121Leu missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.4499A>G p.Asp1500Gly missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.4624C>T p.Arg1542Cys missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.5205C>G p.Asp1735Glu missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.6491A>G p.Asn2164Ser missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.9592C>T p.Gln3198Ter missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.12013T>G p.Phe4005Val missense_variant - Both parents Unknown 31130284 Monies D , et al. (2019)
c.8515C>T p.Arg2839Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.10385C>T p.Ser3462Phe missense_variant Unknown - Unknown 25502226 Ionita-Laza I , et al. (2014)
c.412+1G>T - splice_site_variant Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
c.7441G>A p.Val2481Ile missense_variant Familial Both parents - 23033978 de Ligt J , et al. (2012)
c.1219C>T p.Gln407Ter stop_gained Familial Both parents Simplex 27435318 Charng WL , et al. (2016)
c.2470T>G p.Ser824Ala missense_variant Familial Both parents Simplex 23352163 Yu TW , et al. (2013)
c.2650+2T>G - splice_site_variant Familial Maternal Multiplex 25502226 Ionita-Laza I , et al. (2014)
c.8868-3C>G - splice_region_variant - Both parents Multi-generational 31130284 Monies D , et al. (2019)
c.12042_12045del p.Asn4014LysfsTer3 frameshift_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.7051C>T p.Arg2351Ter stop_gained Unknown Both parents Unknown 12730828 Kolehmainen J , et al. (2003)
c.10223C>G p.Ser3408Ter stop_gained Familial Paternal Multiplex 25502226 Ionita-Laza I , et al. (2014)
c.3G>A p.Met1? initiator_codon_variant Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
c.4572dup p.Glu1525ArgfsTer45 frameshift_variant Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.9592C>T p.Gln3198Ter missense_variant Familial Unknown Multiplex 25502226 Ionita-Laza I , et al. (2014)
- - copy_number_loss Familial Both parents Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5752_5753del p.Leu1918Ter frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3348_3349del p.Cys1117PhefsTer8 frameshift_variant Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.1000del p.Tyr334IlefsTer24 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.9793dup p.Met3265AsnfsTer8 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5426_5427dup p.Gln1810SerfsTer21 frameshift_variant Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.6420_6421del p.Gln2140HisfsTer28 frameshift_variant Unknown - Unknown 12730828 Kolehmainen J , et al. (2003)
c.9667C>T p.Arg3223Trp missense_variant Familial Both parents Multiplex 25502226 Ionita-Laza I , et al. (2014)
c.5590C>T p.Gln1864Ter stop_gained Familial Both parents Multi-generational 27457812 Riazuddin S , et al. (2016)
c.6879del p.Phe2293LeufsTer24 frameshift_variant Familial Both parents Multiplex 26104215 Rafiq MA , et al. (2015)
c.11827_11828insC p.Gly3943AlafsTer49 frameshift_variant Familial Both parents Simplex 23352163 Yu TW , et al. (2013)
c.6879del p.Phe2293LeufsTer24 frameshift_variant Familial Both parents Multi-generational 26104215 Rafiq MA , et al. (2015)
c.401dup p.Asp134GlufsTer12 frameshift_variant Familial Paternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.8978A>G p.Asn2993Ser missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
ENST00000395996:c.*2515+1G>A - splice_site_variant Familial Maternal and paternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

Score Delta: Score remained at S

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

10/1/2017
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

10/1/2016
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

7/1/2016
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

4/1/2016
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.2014] [Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and ...2003] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite ou...2014] [Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.2015] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

7/1/2015
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

1/1/2015
S
icon
S

Increased from S to S

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the VPS13B gene have been identified with Cohen syndrome (Kolehmainen et al., 2003). In the four founder population mutations studied, autistic features vary, with none reported in Finnish patients, 93% in Greek/Mediterranean patients, 50% in Irish travelers and 25% in Amish patients.

Krishnan Probability Score

Score 0.43248124962091

Ranking 20684/25841 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.
ExAC Score

Score 9.810623302116E-27

Ranking 18120/18225 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
Sanders TADA Score

Score 0.95079392972083

Ranking 18631/18665 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).
Zhang D Score

Score 0.4074986667166

Ranking 1375/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
FAM177A1 Protein FAM177A1 Human Protein Binding 283635 Q8N128
LGALS7 Galectin-7 Human Protein Binding 3963 P47929
LYPD4 Ly6/PLAUR domain-containing protein 4 Human Protein Binding 147719 Q6UWN0-2
SNX21 Sorting nexin-21 Human Protein Binding 90203 Q5JZH5
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