POLR1C
protein-codingRNA polymerase I and III subunit C, the group of RNA polymerase subunits
Gene summary
The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~52.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009558
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009558
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009558
Submitter: ClinGen
*POLR1C* was first reported in relation to AR Treacher Collins syndrome 3 in 2011 (Dauwerse et al., PMID: 21131976). Treacher Collins syndrome 3 is a disorder of craniofacial development characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. Variants in *POLR1C* have been reported in individuals with the following disease entities: Treacher Collins syndrome 3 and hypomylenating leukodystrophy 11. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, Treacher Collins syndrome 3 (OMIM:248390) and hypomylenating leukodystrophy 11 (OMIM:616494). The split curation for AR hypomylenating leukodystrophy 11 will be curated separately. Two missense variants, three nonsense variants, and one intronic deletion that have been reported in four probands in four publications (PMIDs: 21131976, 30957429) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by functional alteration of non-patient cells (PMIDs: 29567474). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date July 20th, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0700278
Submitter: ClinGen
*POLR1C*, which encodes a subunit of RNA Polymerase I and III, was first reported in relation to disease in 2011, associated with autosomal recessive Treacher Collins Syndrome 3 (TCS3) (Dauwerse et al., PMID: 21131976). TCS is characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss, with a high degree of phenotypic variability (PMID:21131976). Although the initial publication did not comment on brain imaging, a 2015 publication described individuals with biallelic *POLR1C* variants and hypomyelinating leukodystrophy, designated HLD11 (PMID: 26151409). Subsequent papers reported individuals with leukodystrophy and TCS features (PMIDs 33597727, 32042905, 32319256, 37197783). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern, and we found that the phenotype represents a spectrum. Therefore, TCS3 (OMIM:248390) and HLD11 (OMIM:616494) have been lumped into one disease entity, *POLR1C*-related disorder (MONDO: 0700278). Sixteen variants (missense, nonsense, in-frame indel, frameshift, splice site) reported in 11 probands across 6 publications (PMIDs: 37197783, 32042905, 26151409, 21131976, 33597727, 32319256) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is supported by experimental evidence including protein interaction and an animal model (PMIDs: 26151409, 2744828). Mutations in *POLR3A *and *POLR3B*, which encode two other subunits of RNA Pol III and physically interact with *POLR1C*, are definitively associated with hypomyelinating leukodystrophies (PMID: 26151409). *POLR1C*-knockout zebrafish display TCS features including craniofacial cartilage hypoplasia, mandibular hypoplasia, microcephaly, microphthalmia (PMID 27448281). In summary, there is definitive evidence supporting the relationship between *POLR1C* and autosomal recessive *POLR1C*-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date March 24, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0019505
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014666
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014666
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009558
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0002457
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014666
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014666
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Neurologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POLR1C variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_203290.4. 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 | 46 | 48 | |||
| missense | 7 | 19 | 114 | 6 | 1 | 147 |
| nonsense | 6 | 5 | 1 | 12 | ||
| start loss | 0 | |||||
| frameshift | 6 | 12 | 18 | |||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 1 | 8 | ||
| Total | 20 | 42 | 118 | 52 | 1 | 233 |
Highest pathogenic variant AF is 0.00018027975
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_976035.1 | 9 | MANE Select | |
| Ensembl | ENSP00000496044.1 | 9 | MANE Select | |
| RefSeq | NP_001305805.1 | 9 | Standard | |
| RefSeq | NP_001350587.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| polr1c | Danio rerio | Structure: neuroepithelial cell Quality: apoptotic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyrimidine metabolism - Homo sapiens (human)
- Cytosolic DNA-sensing pathway - Homo sapiens (human)
- RNA polymerase - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
- Epstein-Barr virus infection - Homo sapiens (human)
Biological Process
- transcription by RNA polymerase I
- transcription initiation from RNA polymerase I promoter
- termination of RNA polymerase I transcription
- transcription by RNA polymerase III
- positive regulation of gene expression, epigenetic
Molecular Function
- RNA polymerase I activity
- RNA polymerase III activity
- DNA binding
- DNA-directed 5'-3' RNA polymerase activity
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- RNA polymerase III complex
- RNA polymerase I complex
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372389
- Coding exons
- 9
- Length
- 19884
- Individuals with no LoFs
- 125706
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125748
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.44 | 252 | 195 | 1.29 | 0.0000121 | 2272 |
| Missense (PolyPhen) | 79 | 64.096 | 1.2325 | 734 | ||
| Synonymous | -1.58 | 89 | 71.9 | 1.24 | 0.00000399 | 699 |
| Loss of Function | 0.335 | 15 | 16.5 | 0.911 | 9.74e-7 | 188 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I and III which synthesize ribosomal RNA precursors and small RNAs, such as 5S rRNA and tRNAs, respectively. RPAC1 is part of the Pol core element with the central large cleft and probably a clamp element that moves to open and close the cleft (By similarity). {ECO:0000250|UniProtKB:P07703, ECO:0000305|PubMed:26151409}.;
- Disease
- DISEASE: Treacher Collins syndrome 3 (TCS3) [MIM:248390]: A form of Treacher Collins syndrome, a disorder of craniofacial development. Treacher Collins syndrome is characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. {ECO:0000269|PubMed:21131976, ECO:0000269|PubMed:26151409}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukodystrophy, hypomyelinating, 11 (HLD11) [MIM:616494]: An autosomal recessive neurologic disorder characterized by brain hypomyelination, delayed psychomotor development, intellectual disability, tremor and other neurologic symptoms. Some patients may additionally manifest non-neurologic features, particularly dental abnormalities and hypogonadotropic hypogonadism. {ECO:0000269|PubMed:26151409}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.176
Intolerance Scores
- LoFtool
- 0.292
- RVIS EVS
- -0.09
- RVIS percentile EVS
- 46.74
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.988
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |