CLTC

Gene Facts

• HGNC Symbol: CLTC (HGNC:2092)
• HGNC Name: clathrin heavy chain
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CLTCL2
• Alias symbols: Hc
• %HI: 4.77
• pLI: 1
• LOEUF: 0.1
• Cytoband: 17q23.1
• Genomic Coordinates:

  GRCh37/hg19:	chr17:57697256-57774317
  GRCh38/hg38:	chr17:59619895-59696956

• MANE Select Transcript: NM_004859.4 ENST00000269122.8
• 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 a 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 mai... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-19992
• ClinGen Curation ID: CCID:006885
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 09/27/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 31776469
  Nabais Sa et al (2020) describe 13 individuals with CLTC variants, including three nonsense variants, two frameshift variants, two missense variants , three splice site variants and three in-frame deletions. All were found to be de novo except for one frameshift variant as the father was unavailable for testing (not present in the mother). The nonsense and frame-shift variants were all expected to result in nonsense-mediated messenger RNA (mRNA) decay. They hypothesized that the nonsense and frameshift variants have a different mode of action than the missense and in-frame variants. They stated that a more severe phenotype was more frequently reported in individuals with missense and in-frame CLTC variants than with nonsense and frameshift variants (although the difference was not statistically significant). The authors reported that all individuals presented with motor and/or speech delay. All had ID that varied from mild to severe. Neuropsychiatric features, noted in the majority of individuals (9/12), included attention deficit–hyperactivity disorder (ADHD) (4/9) and autism (3/10). Epilepsy was observed in 5/13. Additional neurologic problems were noted such as hypotonia. The majority of individuals had structural brain abnormalities, craniofacial abnormalities and/or facial dysmorphisms (13/13).
• PUBMED: 26822784
  DeMari et al. (2016) identified a de novo frameshift variant in the CLTC gene in a 3-year-old girl with intellectual disability (ID) and dysmorphic features, postulating haploinsufficiency of CLTC as the pathogenetic mechanism.
• PUBMED: 33041083
  Fernández-Mayoralas et al. (2021) reported a de novo nonsense variant detected by WGS in a girl with periventricular heterotopia. She also had subtle dysmorphism and a history of patent ductus arteriosus and bone alterations (spina bifida occulta and mild rib hypoplasia). The girl was also described as having a small head circumference, epilepsy, and attention and learning difficulties.
• PUBMED: 29100083
  Hamdan et al (2017) performed whole-genome sequencing (WGS) in 197 individuals with unexplained developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. They identified a de novo frameshift variant in an individual with moderate ID associated with severe refractory seizures. There also reported on clinical findings in 11 additional individuals with de novo variants in CLTC; 4 nonsense variants, 3 frameshift, 2 small in-frame deletions, 1 splice site variant, and missense variants. Most of these individuals presented with early-onset hypotonia and GDD, which evolved over time into mild to severe ID (or borderline intelligence). Four individuals also developed ataxia and five had seizures.

• HI Evidence Comments: De novo pathogenic variants in the CLTC gene have been associated with a variable, autosomal dominant complex neurodevelopmental disorder presentation that includes global developmental delay, impaired intellectual development that ranged from borderline to severe, hypotonia, delayed walking, poor fine motor skills, clumsiness, and poor or absent speech. Dysmorphic features, seizures, ataxia, spasticity, paraparesis, acquired microcephaly, oral/motor apraxia, and behavioral abnormalities have also been reported. Whilst there are no whole gene deletions reported in the literature there are several loss of function variants predicted to result in NMD and haploinsufficiency. However, there are also many missense variants suggesting a possible dominant-negative mechanism. The two different mechanisms may reflect the genetic heterogeneity of this condition.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity