Human Gene Module / Chromosome 3 / ITPR1

ITPR1inositol 1,4,5-trisphosphate receptor type 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 18
Rare Variants / Common Variants
27 / 0
Aliases
ITPR1, ACV,  CLA4,  INSP3R1,  IP3R,  IP3R1,  PPP1R94,  SCA15,  SCA16,  SCA29
Associated Syndromes
-
Chromosome Band
3p26.1
Associated Disorders
-
Relevance to Autism

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Molecular Function

This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ITPR1 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
5 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
6 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
7 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No Microcephaly, hypotonia
8 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
9 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
10 Support Genome-wide detection of tandem DNA repeats that are expanded in autism Trost B et al. (2020) Yes -
11 Support - Brunet T et al. (2021) No -
12 Support - Zou D et al. (2021) No -
13 Support - Woodbury-Smith M et al. (2022) Yes -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Sanchis-Juan A et al. (2023) No -
16 Support - Karthika Ajit Valaparambil et al. () No -
17 Support - Marketa Wayhelova et al. (2024) No -
18 Support - Shenglan Li et al. (2024) No -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - minisatellite Unknown - Simplex 32717741 Trost B et al. (2020)
c.5980-17G>A - intron_variant De novo - - 38593811 Shenglan Li et al. (2024)
c.7006C>T p.Pro2336Ser stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.5176-8G>C - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.7516G>A p.Glu2506Lys missense_variant Unknown - - 34145886 Zou D et al. (2021)
c.2794C>T p.Arg932Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4246G>A p.Val1416Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6570G>C p.Glu2190Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6884G>A p.Gly2295Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4900G>A p.Glu1634Lys missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.7739G>A p.Gly2580Glu missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.1409G>C p.Arg470Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.4012G>A p.Asp1338Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.805C>T p.Arg269Trp missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.1127G>A p.Arg376Lys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3765C>T p.Cys1255%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.7578A>G p.Glu2526%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.784G>A p.Val262Ile missense_variant Familial Paternal - 28628100 Geisheker MR , et al. (2017)
c.1594G>A p.Ala532Thr missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2094G>A p.Trp698Ter stop_gained Familial Paternal Simplex 28333917 Vissers LE , et al. (2017)
c.7615G>A p.Gly2539Arg missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3145G>A p.Gly1049Ser missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.5657C>A p.Ala1886Asp missense_variant Familial Maternal Multiplex 30564305 Guo H , et al. (2018)
c.4205C>G p.Thr1402Arg missense_variant De novo - Simplex 38321498 Marketa Wayhelova et al. (2024)
c.799A>G p.Thr267Ala missense_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.805C>T p.Arg269Trp missense_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.7516G>A p.Gly2506Arg missense_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
7/1/2020
3
icon
3

Decreased from 3 to 3

Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[Genome-wide detection of tandem DNA repeats that are expanded in autism2020] [Clustering by phenotype and genome-wide association study in autism2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[New Scoring Scheme]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
1/1/2017
icon
4

Increased from to 4

Description

A likely damaging missense variant in the ITPR1 gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Two additional possibly damaging de novo missense variants in ITPR1 had previously been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014).

Krishnan Probability Score

Score 0.57123219001458

Ranking 802/25841 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 0.99999999999409

Ranking 49/18225 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
Sanders TADA Score

Score 0.62379521501486

Ranking 792/18665 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 0.46817844529485

Ranking 762/20870 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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