CLTC

protein-coding

clathrin heavy chain, the group of Clathrin subunits

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

CLTCL2

MANE transcript

NM_004859.4

Inheritance

ClinVar variants

P:124U:483B:291

Top phenotype

Intellectual developmental disorder, autosomal dominant 56

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr17:59,619,680-59,696,956

External References & Databases

Ensembl (ENSG00000141367)

Transcript & Mutation Effects

hg38 • Region Span ~77.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal dominant 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030922

Submitter: Ambry Genetics

intellectual disability, autosomal dominant 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030922

Submitter: G2P

intellectual disability, autosomal dominant 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030922

Submitter: Illumina

intellectual disability, autosomal dominant 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030922

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

intellectual disability, autosomal dominant 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030922

Submitter: Illumina

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 56AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26822784; 29100083; 31961069

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLTC variants in ClinVar

14 Conditions Cataloged

not providedTotal: 1046

Intellectual disability, autosomal dominant 56Total: 115

Inborn genetic diseasesTotal: 78

CLTC-related disorderTotal: 30

not specifiedTotal: 19

Intellectual disabilityTotal: 3

Global developmental delayTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004859.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar		16 clinvar	270 clinvar	10 clinvar	298
missense	4 clinvar	12 clinvar	453 clinvar	10 clinvar		479
nonsense	27 clinvar	13 clinvar	3 clinvar			43
start loss			1 clinvar			1
frameshift	28 clinvar	25 clinvar	1 clinvar			54
splice donor/acceptor (+/-2bp)	3 clinvar	10 clinvar	9 clinvar	1 clinvar		23
Total	64	60	483	281	10	898

Highest pathogenic variant AF is 0.000009913996

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004859.4	RefSeq	NP_004850.1	32	MANE Select
ENST00000269122.8	Ensembl	ENSP00000269122.3	32	MANE Select
NM_001288653.2	RefSeq	NP_001275582.1	32	Standard
ENST00000393043.5	Ensembl	ENSP00000376763.1	31	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cltca	Danio rerio	Structure: caudal vein plexus Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

cltca

Danio rerio

Structure: caudal vein plexus

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Endocytosis - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human)

Biological Process

mitotic cell cycle
osteoblast differentiation
intracellular protein transport
receptor-mediated endocytosis
autophagy

Molecular Function

RNA binding
double-stranded RNA binding
structural molecule activity
protein binding
protein kinase binding

Cellular Component

lysosome
endosome
spindle
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000269122
Coding exons: 32
Length: 76453
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125740
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	7.76	251	910	0.276	0.0000487	11088
Missense (PolyPhen)		61	376.62	0.16197		4984
Synonymous	1.63	276	313	0.882	0.0000159	3142
Loss of Function	8.31	4	88.2	0.0453	0.00000457	1059

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00048	0.00046	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000036	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. Acts as component of the TACC3/ch- TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter- microtubule bridge (PubMed:15858577, PubMed:16968737, PubMed:21297582). The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:23532825). Plays a role in early autophagosome formation (PubMed:20639872). {ECO:0000269|PubMed:15858577, ECO:0000269|PubMed:16968737, ECO:0000269|PubMed:20639872, ECO:0000269|PubMed:21297582, ECO:0000269|PubMed:23532825}.;
Disease: DISEASE: Mental retardation, autosomal dominant 56 (MRD56) [MIM:617854]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:26822784, ECO:0000269|PubMed:29100083}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.946

Intolerance Scores

LoFtool: 0.190
RVIS EVS: -1.31
RVIS percentile EVS: 4.85

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.959

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium