Human Gene Module / Chromosome X / TRPC5

TRPC5transient receptor potential cation channel subfamily C member 5

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 9
Rare Variants / Common Variants
18 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq23
Associated Disorders
-
Relevance to Autism

Diagnostic exome sequencing in 100 patients with severe intellectual disability (ID) and their parents in de Ligt et al., 2012 identified a maternally-inherited missense variant in the TRPC5 gene in a male ID proband who was also diagnosed with autism spectrum disorder (ASD) and Tourette syndrome. Analysis of 54 male patients presenting with intellectual disability (ID) and a family history suggesting X-linked inheritance or maternal skewed X-chromosome inactivation using an X-chromosome-specific microarray in Mignon-Ravix et al., 2014 identified a deletion of the first exon of the TRPC5 gene in a child presenting with ID and autism spectrum disorder (ASD). Leitao et al., 2022 presented four previously unreported individuals with TRPC5 variants: three brothers with ASD and intellectual disability with a maternally-inherited missense variant that was experimentally confirmed to result in a constitutively active current; and a male patient with high-functioning ASD with a maternally-inherited nonsense variant. De novo coding variants in TRPC5 have also been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), in patients with DD/ID (Deciphering Developmental Disorders Study 2015; Lelieveld et al., 2016), and in a proband with congenital heart disease (Homsy et al., 2015).

Molecular Function

This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1).

External Links
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Human
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Mouse
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SFARI Genomic Platforms
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Reports related to TRPC5 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Diagnostic exome sequencing in persons with severe intellectual disability de Ligt J , et al. (2012) Yes -
2 Support - Mignon-Ravix C et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Homsy J , et al. (2016) No -
5 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
6 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
7 Recent Recommendation - Leito E et al. (2022) Yes -
8 Recent recommendation - Yongxiang Li et al. (2024) Yes Anxiety, depression
9 Support - Ashlesha Gogate et al. (2024) Yes -
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.212G>A p.Arg71Gln missense_variant De novo - - 28135719 et al. (2017)
- - copy_number_loss Familial Maternal - 24817631 Mignon-Ravix C et al. (2014)
c.571C>T p.Arg191Cys missense_variant De novo - - 26785492 Homsy J , et al. (2016)
- - copy_number_loss Familial Maternal Multiplex 38959890 Yongxiang Li et al. (2024)
c.401C>T p.Thr134Met missense_variant Unknown - - 38959890 Yongxiang Li et al. (2024)
c.2014T>C p.Tyr672His missense_variant Unknown - - 38959890 Yongxiang Li et al. (2024)
c.2212C>A p.Leu738Ile missense_variant Unknown - - 38959890 Yongxiang Li et al. (2024)
c.2609G>A p.Gly870Glu missense_variant Unknown - - 38959890 Yongxiang Li et al. (2024)
c.2651C>T p.Ser884Phe missense_variant Unknown - - 38959890 Yongxiang Li et al. (2024)
c.2677G>A p.Ala893Thr missense_variant Unknown - - 38959890 Yongxiang Li et al. (2024)
c.100_102del p.Lys34del inframe_deletion Unknown - - 38959890 Yongxiang Li et al. (2024)
c.540G>A p.Glu180= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.965G>A p.Trp322Ter stop_gained Familial Maternal Simplex 36323681 Leito E et al. (2022)
c.1114G>T p.Ala372Ser missense_variant De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.2386A>T p.Ser796Cys missense_variant De novo - Simplex 39632905 Ashlesha Gogate et al. (2024)
c.523C>T p.Arg175Cys missense_variant Familial Maternal Multiplex 36323681 Leito E et al. (2022)
c.1999C>A p.Pro667Thr missense_variant Familial Maternal Simplex 23033978 de Ligt J , et al. (2012)
c.1469C>T p.Ser490Leu missense_variant Familial Maternal Simplex 39632905 Ashlesha Gogate et al. (2024)
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.

1/1/2023
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49560421262268

Ranking 2881/25841 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 0.99363609848607

Ranking 1626/18225 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 0.94320776854846

Ranking 15599/18665 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 -0.15670206241795

Ranking 14329/20870 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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