Human Gene Module / Chromosome 17 / CLTC

CLTCclathrin heavy chain

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
20 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
17q23.1
Associated Disorders
-
Relevance to Autism

CLTC was classified as an ASD candidate gene in males in Kim et al., 2024 following a combined TADA analysis consisting of a novel Korean ASD cohort in addition to the Simons Simplex Collection and the SPARK cohort. De novo ASD-associated variants in CLTC included three de novo loss-of-function variants (two in probands from the Autism Sequencing Consortium, one in a proband from the MSSNG cohort), a de novo missense variant predicted to be deleterious by REVEL and MPC in a SPARK proband, and a de novo missense variant with a CADD score > 20 in a Korean ASD proband (De Rubeis et al., 2012; Satterstrom et al., 2020; Zhou et al., 2022; Wang et al., 2023; Kim et al., 2024). Heterozygous mutations in this gene are also responsible for autosomal dominant intellectual developmental disorder-56 (MRD56; OMIM 617854); autism reported in 3/10 individuals with de novo CLTC variants in Nabais S et al., 2020.

Molecular Function

Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. The basic subunit of the clathrin coat is composed of three heavy chains and three light chains.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CLTC (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support - Maria J Nabais Sá et al. (2020) No ASD, ADHD
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Wang J et al. (2023) Yes -
6 Primary - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4717T>C p.Cys1573Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1962C>G p.Tyr654Ter stop_gained De novo - - 31981491 Satterstrom FK et al. (2020)
c.445G>T p.Ala149Ser missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.3048T>C p.Ser1016= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.4133T>C p.Met1378Thr missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.2272C>T p.Arg758Ter stop_gained De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.4366C>T p.Gln1456Ter stop_gained De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.4615C>T p.Gln1539Ter stop_gained De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.2919+1G>C p.? splice_site_variant De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.3065+1G>A p.? splice_site_variant De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.3766-2A>G p.? splice_site_variant De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.430dup p.Arg144ProfsTer4 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2669C>T p.Pro890Leu missense_variant De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.3765G>C p.Glu1255Asp missense_variant De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.1953del p.Val652SerfsTer9 frameshift_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2325_2327del p.Ile776del inframe_deletion De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.2794_2796del p.Asn932del inframe_deletion De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.3621_3623del p.Asp1207del inframe_deletion De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.1226del p.Gly409ValfsTer25 frameshift_variant De novo - - 31776469 Maria J Nabais Sá et al. (2020)
c.4481del p.Ser1494CysfsTer32 frameshift_variant Unknown Not maternal - 31776469 Maria J Nabais Sá et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.50337263639699

Ranking 1949/25841 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 0.99999999331335

Ranking 127/18225 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 0.92917079268886

Ranking 11099/18665 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 0.30692400577349

Ranking 2631/20870 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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