Human Gene Module / Chromosome 22 / CLTCL1

CLTCL1clathrin, heavy chain-like 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
24 / 0
Aliases
CLTCL1, CHC22,  CLH22,  CLTCL,  CLTD,  FLJ36032
Associated Syndromes
-
Chromosome Band
22q11.21
Associated Disorders
-
Relevance to Autism

A homozygous mutation in the CLTCL1 gene was found to segregate perfectly with disease in a multiplex ASD family. No homozygotes for his mutation were observed in 1328 control chromosomes. Seven additional compound heterozygous mutations in the CLTCL1 gene were identified in ASD cases from the replication cohort that were not observed in 371 controls (Chahrour et al., 2012).

Molecular Function

Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CLTCL1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism Chahrour MH , et al. (2012) Yes -
2 Support A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing Hu X , et al. (2013) No -
3 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families Egger G , et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
5 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (24)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Paternal - 24643514 Egger G , et al. (2014)
c.1219C>T p.Gln407Ter stop_gained Unknown - Unknown 24126932 Hu X , et al. (2013)
c.3878G>A p.Arg1293His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4487C>G p.Ala1496Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.182C>T p.Pro61Leu missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.313G>A p.Ala105Thr missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.614A>G p.Lys205Arg missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.988G>A p.Glu330Lys missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.1721G>A p.Arg574His missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.2071G>A p.Glu691Lys missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.2822A>G p.Lys941Arg missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.1912A>T p.Arg638Trp missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1921G>A p.Val641Ile missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.3928G>A p.Glu1310Lys missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.3932G>A p.Arg1311Gln missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.4774G>A p.Val1592Met missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.4859G>A p.Arg1620His missense_variant Familial - - 22511880 Chahrour MH , et al. (2012)
c.2413C>T p.Gln805Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
G>A p.Arg125Cys missense_variant Familial Both parents Multiplex 22511880 Chahrour MH , et al. (2012)
c.4122dup p.Val1375CysfsTer10 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.108_109insA p.Phe37IlefsTer10 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1941T>A p.Asn647Lys missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.208_209del p.Ser70CysfsTer8 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4309_4310insA p.Ser1437LysfsTer29 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

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 rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A rare homozygous R125C mutation in the CLTCL1 gene was found to segregate perfectly with disease in a single multiplex ASD family (PMID 22511880). No homozygotes for this mutation were observed in 1328 control chromosomes. In a case-control screen for additional mutations, compound heterozygous mutations in the CLTCL1 gene were identified in 17/418 ASD cases and 6/371 controls.

Reports Added
[Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014]
Krishnan Probability Score

Score 0.4471448961076

Ranking 13979/25841 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 1.2407556782992E-26

Ranking 18119/18225 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 0.94973554085696

Ranking 18211/18665 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
Larsen Cumulative Evidence Score

Score 31

Ranking 69/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C4ORF6 Uncharacterized protein encoded by LINC01587 Human Protein Binding Q99440
CCDC27 Coiled-coil domain-containing protein 27 Human Protein Binding 148870 Q2M243
CCDC69 cDNA FLJ13705 fis, clone PLACE2000302 Human Protein Binding Q9H8E5
CCL21 C-C motif chemokine 21 Human Protein Binding 6366 O00585
CLINT1 clathrin interactor 1 Human Protein Binding 9685 Q14677
CTSL1 Cathepsin L1 Human Protein Binding 1514 P07711
GLTSCR2 glioma tumor suppressor candidate region gene 2 Human Protein Binding 29997 Q9NZM5
PICALM phosphatidylinositol binding clathrin assembly protein Human Protein Binding 8301 Q13492
PRKAG3 5'-AMP-activated protein kinase subunit gamma-3 Human Protein Binding 53632 Q9UGI9
PVRIG Transmembrane protein PVRIG Human Protein Binding 79037 Q6DKI7
RAB32 Ras-related protein Rab-32 Human Protein Binding 10981 Q13637
RPL6 ribosomal protein L6 Human Protein Binding 6128 Q02878
SLC2A4 solute carrier family 2 (facilitated glucose transporter), member 4 Human Protein Binding 6517 P14672
SLC37A3 solute carrier family 37 (glycerol-3-phosphate transporter), member 3 Human Protein Binding 84255 Q8NCC5
STAMBPL1 STAM binding protein-like 1 Human Protein Binding 57559 Q96FJ0
TCP10L T-complex protein 10A homolog 2 Human Protein Binding 140290 Q8TDR4
TMEM199 transmembrane protein 199 Human Protein Binding 147007 Q8N511
TTC30A tetratricopeptide repeat domain 30A Human Protein Binding 92104 Q86WT1
TTC30B tetratricopeptide repeat domain 30B Human Protein Binding 150737 Q8N4P2
TTC9B Tetratricopeptide repeat protein 9B Human Protein Binding 148014 Q8N6N2
ZNF169 Zinc finger protein 169 Human Protein Binding 169841 Q14929
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