Human Gene Module / Chromosome 22 / SHANK3

SHANK3SH3 and multiple ankyrin repeat domains 3

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
28 / 61
Rare Variants / Common Variants
233 / 8
Aliases
SHANK3, PSAP2,  PROSAP2,  SPANK-2,  KIAA1650
Associated Syndromes
Phelan-McDermid syndrome, Rett syndrome-like phenotype
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Chromosome Band
22q13.33
Associated Disorders
DD/NDD, ASD, ID, EPS
Relevance to Autism

Recurrent mutations in the SHANK3 gene have been identified in multiple individuals with ASD as described below. SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).

Molecular Function

Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.

Reports related to SHANK3 (61 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Boeckers TM , et al. (1999) No -
2 Recent Recommendation An architectural framework that may lie at the core of the postsynaptic density. Baron MK , et al. (2006) No -
3 Primary Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Durand CM , et al. (2006) Yes -
4 Support Contribution of SHANK3 mutations to autism spectrum disorder. Moessner R , et al. (2007) Yes -
5 Recent Recommendation Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. Hung AY , et al. (2008) No -
6 Recent Recommendation Heterogeneous dysregulation of microRNAs across the autism spectrum. Abu-Elneel K , et al. (2008) No -
7 Support Novel de novo SHANK3 mutation in autistic patients. Gauthier J , et al. (2008) Yes -
8 Negative Association Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection. Sykes NH , et al. (2009) Yes -
9 Recent Recommendation Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3. Delahaye A , et al. (2009) No -
10 Recent Recommendation ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3. Liebau S , et al. (2009) No -
11 Negative Association Association study of SHANK3 gene polymorphisms with autism in Chinese Han population. Qin J , et al. (2009) Yes -
12 Recent Recommendation Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease. Gong Y , et al. (2009) No -
13 Recent Recommendation Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses. Schmeisser MJ , et al. (2009) No -
14 Recent Recommendation 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Dhar SU , et al. (2010) No MR
15 Recent Recommendation De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Gauthier J , et al. (2010) No -
16 Support Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Awadalla P , et al. (2010) Yes -
17 Negative association Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities. Kolevzon A , et al. (2010) Yes -
18 Support Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development. Waga C , et al. (2011) Yes -
19 Recent Recommendation Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Pea J , et al. (2011) No -
20 Negative association Association study of the CNS patterning genes and autism in Han Chinese in Taiwan. Chien YL , et al. (2011) Yes -
21 Support SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Durand CM , et al. (2011) No -
22 Support Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Schaaf CP , et al. (2011) Yes -
23 Support High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. Kelleher RJ 3rd , et al. (2012) Yes -
24 Recent Recommendation Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Boccuto L , et al. (2012) Yes -
25 Support Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Vucurovic K , et al. (2012) No ID
26 Negative association Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. Liu Y , et al. (2013) Yes -
27 Recent Recommendation Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation. Raynaud F , et al. (2013) No -
28 Recent Recommendation Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Soorya L , et al. (2013) Yes ID, epilepsy/seizures
29 Recent Recommendation SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. Mameza MG , et al. (2013) Yes -
30 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
31 Recent Recommendation Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. Duffney LJ , et al. (2013) No -
32 Recent Recommendation Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Zhu L , et al. (2013) No -
33 Recent Recommendation The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation. Grabrucker S , et al. (2014) No -
34 Positive association A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chine... Shao S , et al. (2014) Yes -
35 Recent recommendation Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing aut... Wang X , et al. (2014) No -
36 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
37 Recent recommendation Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. Leblond CS , et al. (2014) Yes -
38 Support Refining analyses of copy number variation identifies specific genes associated with developmental delay. Coe BP , et al. (2014) Yes -
39 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
40 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No Speech delay
41 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
42 Support Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder. Nemirovsky SI , et al. (2015) Yes -
43 Recent recommendation Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption... Kozol RA , et al. (2015) No -
44 Support De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient. Hara M , et al. (2015) No DD, autistic features, stereotyped hand movements,
45 Support Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. Cochoy DM , et al. (2015) Yes -
46 Recent recommendation Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits. Speed HE , et al. (2015) No -
47 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
48 Support Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum dis... Philippe A , et al. (2015) No Developmental regression
49 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
50 Recent recommendation Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Yi F , et al. (2016) No -
51 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
52 Support Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor. Breckpot J , et al. (2016) No -
53 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
54 Support The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations. Holder JL Jr and Quach MM (2016) No -
55 Recent recommendation Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength. Arons MH , et al. (2016) No -
56 Positive association A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3. Connolly S , et al. (2016) Yes -
57 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
58 Support Investigation of SHANK3 in schizophrenia. de Sena Cortabitarte A , et al. (2017) No -
59 Support Neurogenetic analysis of childhood disintegrative disorder. Gupta AR , et al. (2017) No -
60 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
61 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
Rare Variants   (233)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 17173049 Durand CM , et al. (2006)
c.3680insG p.Ala1227Glyfs frameshift_variant De novo - Multiplex 17173049 Durand CM , et al. (2006)
- - copy_number_loss - - - 17173049 Durand CM , et al. (2006)
- - copy_number_gain - - - 17173049 Durand CM , et al. (2006)
c.34C>T p.Arg12Cys missense_variant Familial Maternal Multiplex 17173049 Durand CM , et al. (2006)
c.593C>G p.Ala198Gly missense_variant Familial Maternal Multiplex 17173049 Durand CM , et al. (2006)
c.898C>T p.Arg300Cys missense_variant Familial Maternal Simplex 17173049 Durand CM , et al. (2006)
c.3032G>T p.Gly1011Val missense_variant Familial - Unknown 17173049 Durand CM , et al. (2006)
- p.Arg1066Leu missense_variant Familial Maternal Simplex 17173049 Durand CM , et al. (2006)
c.3692G>A p.Arg1231His missense_variant Familial Maternal Multiplex 17173049 Durand CM , et al. (2006)
- p.Ser1566Gly missense_variant Familial Paternal Simplex 17173049 Durand CM , et al. (2006)
c.962A>G p.Gln321Arg missense_variant De novo - Simplex 17999366 Moessner R , et al. (2007)
c.1022C>T p.Ser341Leu missense_variant Familial Paternal Simplex 17999366 Moessner R , et al. (2007)
c.2908G>T p.Ala970Ser missense_variant Familial Paternal Simplex 17999366 Moessner R , et al. (2007)
c.3517G>A p.Ala1173Thr missense_variant Familial Maternal Multiplex 17999366 Moessner R , et al. (2007)
c.3788C>T p.Pro1263Leu missense_variant Familial Paternal Simplex 17999366 Moessner R , et al. (2007)
c.4216C>G p.Leu1406Val missense_variant Familial Maternal Multiplex 17999366 Moessner R , et al. (2007)
c.4328T>C p.Met1443Thr missense_variant Familial Maternal Simplex 17999366 Moessner R , et al. (2007)
Del4358-4372 Del of 5 aa inframe_deletion Familial Maternal Multiplex 17999366 Moessner R , et al. (2007)
c.4669G>A p.Gly1557Ser missense_variant Familial Paternal Simplex 17999366 Moessner R , et al. (2007)
c.4960C>A p.Pro1654Thr missense_variant Familial Paternal Multiplex 17999366 Moessner R , et al. (2007)
c.4960C>A p.Pro1654Thr missense_variant Familial Maternal Multiplex 17999366 Moessner R , et al. (2007)
- - copy_number_loss De novo - Simplex 17999366 Moessner R , et al. (2007)
- - copy_number_loss Familial Paternal Simplex 17999366 Moessner R , et al. (2007)
- - copy_number_loss De novo - Multiplex 17999366 Moessner R , et al. (2007)
c.203T>C p.Leu68Pro missense_variant Familial Paternal Simplex 18615476 Gauthier J , et al. (2008)
c.670G>A p.Ala224Thr missense_variant Unknown - Unknown 18615476 Gauthier J , et al. (2008)
c.2161G>A p.Ala721Thr missense_variant Unknown - Unknown 18615476 Gauthier J , et al. (2008)
c.2265C+1delG p.Ser755SerfsTer1 splice_site_variant De novo - Simplex 18615476 Gauthier J , et al. (2008)
c.3893G>A p.Arg1298Lys missense_variant Familial Maternal - 18615476 Gauthier J , et al. (2008)
c.4960C>A p.Pro1654Thr missense_variant Unknown - Unknown 18615476 Gauthier J , et al. (2008)
c.734T>C p.Ile245Thr missense_variant Unknown - Unknown 18615476 Gauthier J , et al. (2008)
- - copy_number_loss De novo - Simplex 19454329 Delahaye A , et al. (2009)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
- - copy_number_loss - - - 20186804 Dhar SU , et al. (2010)
c.3349C>T p.Arg1117Ter stop_gained De novo - Multiplex 20385823 Gauthier J , et al. (2010)
c.1606C>T p.Arg536Trp missense_variant De novo - - 20385823 Gauthier J , et al. (2010)
c.1023G>A p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.1479C>G p.His494Gln missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.1893C>T p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.2043C>G p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.2856G>C p.Ser952Thr missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.3032G>T p.Gly1011Val missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.3066G>A p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.3401C>A p.Pro1134His missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.3482T>C p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.3558G>A p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.734T>C p.Ile245Thr missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.2161G>A p.Ala721Thr missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.2310G>A p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.2997C>T p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.3363C>T p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.3999T>G p.Val1333Gly missense_variant - - - 20385823 Gauthier J , et al. (2010)
c.4947C>T p.(=) synonymous_variant - - - 20385823 Gauthier J , et al. (2010)
c.4960C>A p.Pro1654Thr missense_variant - - - 20385823 Gauthier J , et al. (2010)
del(G) Splice-site splice_site_variant De novo - - 20797689 Awadalla P , et al. (2010)
c.1606C>T p.Arg536Trp missense_variant De novo - - 20797689 Awadalla P , et al. (2010)
c.3349C>T p.Arg1117Ter stop_gained De novo - - 20797689 Awadalla P , et al. (2010)
c.1339_1340insG p.Ala447GlyfsTer57 frameshift_variant Familial Maternal - 21062623 Kolevzon A , et al. (2010)
c.1320_1338del18 p.delGlyProGlyProAlaPro inframe_deletion Familial Maternal - 21378602 Waga C , et al. (2011)
c.1967G>A p.Arg656His missense_variant Familial Paternal - 21378602 Waga C , et al. (2011)
N/A N/A intron_variant - - - 21378602 Waga C , et al. (2011)
N/A N/A intron_variant - - - 21378602 Waga C , et al. (2011)
N/A N/A intron_variant De novo - - 21378602 Waga C , et al. (2011)
- - copy_number_loss Familial Maternal - 21378602 Waga C , et al. (2011)
N/A N/A inframe_insertion - - - 21378602 Waga C , et al. (2011)
c.734T>C p.Ile245Thr missense_variant - - - 21378602 Waga C , et al. (2011)
c.3517G>A p.Ala1173Thr missense_variant - - - 21378602 Waga C , et al. (2011)
c.3788G>T p.Pro1263Leu missense_variant - - - 21378602 Waga C , et al. (2011)
c.750C>T p.(=) synonymous_variant - - - 21378602 Waga C , et al. (2011)
c.1563G>A p.(=) synonymous_variant - - - 21378602 Waga C , et al. (2011)
c.4446G>A p.(=) synonymous_variant - - - 21378602 Waga C , et al. (2011)
c.4908C>T p.(=) synonymous_variant - - - 21378602 Waga C , et al. (2011)
c.4935C>T p.(=) synonymous_variant - - - 21378602 Waga C , et al. (2011)
c.483C>T p.(=) synonymous_variant - - - 21378602 Waga C , et al. (2011)
c.3581G>A p.Gly1194Asp missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.3715A>T p.Ser1239Cys missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.3893G>A p.Arg1298Lys missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4018G>A p.Ala1340Thr missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4621C>T p.Pro1541Ser missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4673C>T p.Ala1558Val missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4778A>T p.Thr1593Ile missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4856G>A p.Arg1619His missense_variant Unknown Not paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.4873A>T p.Pro1625Ser missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4877C>T p.Ser1626Lys missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4894G>A p.Ala1632Thr missense_variant Unknown Not paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.4913G>A p.Gly1638Asp missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4960C>A p.Pro1654Thr missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.522C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.612C>A p.Asp204Glu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.763C>T p.His255Tyr missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.769-7C>G - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.898C>T p.Arg300Cys missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.920C>G p.Ala307Gly missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1031-14C>T - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1254G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1315C>T p.Pro439Ser missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1335G>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1337G>T p.Gly446Val missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2077+10C>A - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2313+20G>A - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2398+11G>A - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.249G>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3360C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3708G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3761C>T p.Ala1254Val missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3764C>T p.Pro1255Leu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3765G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3836C>T p.Pro1279Leu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4025C>T p.Pro1342Leu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4050C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4368C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4405G>C p.Gly1469Arg missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4406G>T p.Gly1469Val missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4479C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4490G>A p.Arg1497Gln missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4641C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4720G>A p.Gly1574Arg missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.5106C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
- - copy_number_loss De novo - - 22892527 Boccuto L , et al. (2012)
c.1339_1340insG p.Ala447fsTer503 frameshift_variant Familial Paternal Possible multi-generational 22892527 Boccuto L , et al. (2012)
c.3931delG p.Glu1311fsTer1401 frameshift_variant Unknown (not maternal) - - 22892527 Boccuto L , et al. (2012)
c.421C>G p.Pro141Ala missense_variant De novo - - 22892527 Boccuto L , et al. (2012)
c.1820-4G>A - splice_site_variant Familial Maternal - 22892527 Boccuto L , et al. (2012)
c.4402G>T p.Ala1468Ser missense_variant Unknown - - 22892527 Boccuto L , et al. (2012)
- - copy_number_loss De novo - Simplex 22922660 Vucurovic K , et al. (2012)
- - copy_number_loss Unknown (not maternal) - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss Unknown (not maternal) - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss Unknown (not paternal) - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss Unknown (not paternal) - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss De novo - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss Unknown (not paternal) - - 23758760 Soorya L , et al. (2013)
- - copy_number_loss Unknown (not maternal) - - 23758760 Soorya L , et al. (2013)
c.2497delG p.Pro834ArgfsTer59 frameshift_variant De novo - - 23758760 Soorya L , et al. (2013)
c.1527G>A p.Trp509Ter stop_gained De novo - - 23758760 Soorya L , et al. (2013)
c.3169C>T p.Leu1057Phe missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.2955_2970dup p.Pro992ArgfsTer325 frameshift_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.2425G>T p.Glu809Ter stop_gained De novo - Simplex 25188300 Leblond CS , et al. (2014)
delCCCTG p.Ala1076GlufsTer218 frameshift_variant De novo - Simplex 25188300 Leblond CS , et al. (2014)
delCT p.Leu1142ValfsTer153 frameshift_variant De novo - Simplex 25188300 Leblond CS , et al. (2014)
delCCCT p.Ser1202CysfsTer81 frameshift_variant De novo - Simplex 25188300 Leblond CS , et al. (2014)
delGGGCCCAGCCCCC p.Arg1255LeufsTer25 frameshift_variant De novo - Simplex 25188300 Leblond CS , et al. (2014)
insGGCCA p.Gly1271AlafsTer15 frameshift_variant De novo - Simplex 25188300 Leblond CS , et al. (2014)
c.3727C>T p.Gln1243Ter stop_gained De novo - Simplex 25188300 Leblond CS , et al. (2014)
delC p.Pro1005ArgfsTer73 frameshift_variant Unknown Not maternal Simplex 25188300 Leblond CS , et al. (2014)
delAG p.Gly1339GlufsTer5 frameshift_variant Unknown Not maternal Simplex 25188300 Leblond CS , et al. (2014)
delCCCGGCCCCGCG p.Pro442_Ala445del inframe_deletion Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.1682C>T p.Ser561Leu missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.2254G>A p.Ala752Thr missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.2685T>C p.Leu895Pro missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.3032G>T p.Gly1011Val missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.3704C>A p.Pro1235Gln missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.3796G>A p.Ala1266Thr missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.3825A>T p.Glu1275Asp missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
- - copy_number_loss De novo - Simplex 25188300 Leblond CS , et al. (2014)
- - copy_number_loss De novo - - 25188300 Leblond CS , et al. (2014)
- - copy_number_loss De novo - - 25188300 Leblond CS , et al. (2014)
- - copy_number_loss Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.1485G>A p.Trp495Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1834_1835insGG p.Thr612fs frameshift_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2027G>A p.Arg676His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3866C>T p.Pro1289Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3869C>T p.Ala1290Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1575C>A p.Cys525Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.920C>G p.Ala307Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.985T>A p.Phe329Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2024G>A p.Arg675Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4391G>A p.Arg1464His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2060G>T p.Ser687Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.925_926delAG p.Arg309GlyfsTer21 frameshift_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.3259delC p.Ser1088ProfsTer6 frameshift_variant De novo - Multiplex 25646853 Nemirovsky SI , et al. (2015)
c.3100delC p.Ala1034fsTer44 frameshift_variant De novo - Simplex 25931020 Hara M , et al. (2015)
c.5008A>T p.Lys1670Ter stop_gained Unknown Not maternal - 26045941 Cochoy DM , et al. (2015)
- - copy_number_loss Unknown Not maternal - 26489495 Philippe A , et al. (2015)
c.3598G>C p.Ala1200Pro missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.3727dup p.Ala1243fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
- - copy_number_loss De novo - - 27519580 Breckpot J , et al. (2016)
- - copy_number_loss Unknown - - 27519580 Breckpot J , et al. (2016)
c.4491dupG p.Leu1497fs frameshift_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
G>A p.? splice_site_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.962A>G p.Gln321Arg missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.2808dupC p.Arg936fs frameshift_variant Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
delG - frameshift_variant De novo (mosaic) - Multiplex 28263302 C Yuen RK , et al. (2017)
c.484G>A p.Ala162Thr missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.3032G>T p.Gly1011Val missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.3067C>T p.Arg1023Trp missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.3179C>G p.Thr1060Ser missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.3568G>A p.Asp1190Asn missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.3764G>A p.Arg1255Gln missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.4385G>T p.Arg1462Leu missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.4954G>A p.Gly1652Ser missense_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.2889G>C p.(=) synonymous_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.4947C>T p.(=) synonymous_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.63+148G>A - intron_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.*27C>T - 3_prime_UTR_variant Unknown - - 28371232 de Sena Cortabitarte A , et al. (2017)
G>A p.[Gly277Arg];[Gly277Arg] missense_variant;missense_variant Familial Both parents Simplex 28392909 Gupta AR , et al. (2017)
c.1010C>G p.Thr337Ser missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
C>G p.Arg1271Gly missense_variant De novo - - 28714951 Lim ET , et al. (2017)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1304+48C>T - intron_variant - - - 22892527 Boccuto L , et al. (2012)
c.734T>C p.Ile245Thr missense_variant - - - 24398551 Shao S , et al. (2014)
c.2134+407G>A - intron_variant - - - 27876814 Connolly S , et al. (2016)
c.886-60C>G - intron_variant - - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.1612+18T>C - intron_variant - - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.1797G>A p.(=) synonymous_variant - - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.2161G>A p.Ala721Thr missense_variant - - - 28371232 de Sena Cortabitarte A , et al. (2017)
c.4947C>T p.(=) synonymous_variant - - - 28371232 de Sena Cortabitarte A , et al. (2017)
SFARI Gene score
1S

High Confidence, Syndromic

SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

07-01-2017
1S

Initial score established: 1S

Description

SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).

CNVs associated with SHANK3(1 CNVs)
22q13.33 49 Deletion-Duplication 74  /  206
Animal Models associated with SHANK3(38 Models)
SHANK3_10_KI_HM Genetic
SHANK3_11_KI_HT Genetic
SHANK3_12_KI_HM_reversed RESCUE-Genetic
SHANK3_13_KO_HM Genetic
SHANK3_13_KO_HT Genetic
SHANK3_15_KI_HM Genetic
SHANK3_15_KI_HT Genetic
SHANK3_17_KI_HM Genetic
SHANK3_17_KI_HT Genetic
SHANK3_19_KO_HM Genetic
SHANK3_19_KO_HM_CDPPB-1 RESCUE-Pharmaceutical
SHANK3_19_KO_HM_CDPPB-2 RESCUE-Pharmaceutical
SHANK3_19_KO_HM_MPEP RESCUE-Pharmaceutical
SHANK3_19_KO_HT Genetic
SHANK3_1_KO_HM Genetic
SHANK3_1_KO_HT Genetic
SHANK3_20_CKO_HM_NAc Genetic
SHANK3_21_KO_HM Genetic
SHANK3_22_KO_HM_CreER Genetic
SHANK3_22_KO_HM_CreER-Tx-1 RESCUE-Genetic
SHANK3_22_KO_HM_CreER-Tx-2. RESCUE-Genetic
SHANK3_2_CN_KO_HT_IGF1_H RESCUE-Pharmaceutical
SHANK3_2_CN_KO_HT_IGF1_L RESCUE-Pharmaceutical
SHANK3_2_CN_KO_HT_pIGF1 RESCUE-Pharmaceutical
SHANK3_3_CN_KO_HT Genetic
SHANK3_4_KO_HM Genetic
SHANK3_4_KO_HT Genetic
SHANK3_5_KO_HM Genetic
SHANK3_6_KO_HM Genetic
SHANK3_7_KO_HM Genetic
SHANK3_8_KO_HM Genetic
SHANK3_8_KO_HM_TG003 RESCUE-Pharmaceutical
SHANK3_8_KO_HT Genetic
SHANK3_8_KO_HT_TG003 RESCUE-Pharmaceutical
SHANK3_9_KO_HT_HSV-CA-Rac1 RESCUE-Biological
SHANK3_9_KO_HT_TATcofilin-1 RESCUE-Pharmaceutical
SHANK3_9_KO_HT_TATcofilin-2 RESCUE-Pharmaceutical
SHANK3_9_KO_HT_TATcofilin-3 RESCUE-Pharmaceutical
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AGAP7 ArfGAP with GTPase domain, ankyrin repeat and PH domain 7 Human Protein Binding 653268 Q5VUJ5
C6orf154 chromosome 6 open reading frame 154 Human Protein Binding 221424 Q5JTD7
CA10 carbonic anhydrase X Human Protein Binding 56934 Q9NS85
FRS3 fibroblast growth factor receptor substrate 3 Human Protein Binding 10817 O43559
HECW1 HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 Human Protein Binding 23072 Q76N89
IGSF9 immunoglobulin superfamily, member 9 Human Protein Binding 57549 Q9P2J2
ITGBL1 integrin, beta-like 1 (with EGF-like repeat domains) Human Protein Binding 9358 O95965
LOC727948 LOC727948similar to KIAA0454 protein Human Protein Binding 727948 N/A
MEGF11 multiple EGF-like-domains 11 Human Protein Binding 84465 A6BM72
N4BP3 NEDD4 binding protein 3 Human Protein Binding 23138 O15049
PLEKHA4 pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 4 Human Protein Binding 57664 Q9H4M7
PPP2R3B protein phosphatase 2, regulatory subunit B'', beta Human Protein Binding 28227 Q9Y5P8
ROA0 Heterogeneous nuclear ribonucleoprotein A0 Mouse Protein Binding 77134 Q9CX86
ROA2 Heterogeneous nuclear ribonucleoproteins A2/B1 Mouse Protein Binding 102642938 O88569
ROA3 Heterogeneous nuclear ribonucleoprotein A3 Mouse Protein Binding 229279 Q8BG05
RUNDC3A RUN domain containing 3A Human Protein Binding 10900 Q59EK9
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