COL11A2
protein-codingcollagen type XI alpha 2 chain, the group of Collagens
Gene summary
This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]
- DFNA13
- DFNB53
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~29.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019588
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011159
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008975
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016068
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012333
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011159
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008490
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0044206
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008490
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008490
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008490
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0044206
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0044206
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012333
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008975
Submitter: ClinGen
The COL11A2 gene has been reported in association with multiple conditions and inheritance patterns. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in variant type, inheritance pattern, and phenotype within reported COL11A2 cases. Therefore we have split curations by inheritance pattern and again by nonsyndromic hearing loss and otospondylomegaepiphyseal dysplasia and assessed separately. This assessment focuses on its association to autosomal dominant otospondylomegaepiphyseal dysplasia . The COL11A2 gene was first associated with autosomal dominant otospondylomegaepiphyseal dysplasia in humans as early as 1995 (Vikkula et al.). At least 7 variants in 7 probands (missense, in-frame intel, splice site, nonsense, small deletion) have been reported in humans (PMIDs: 7859284, 9506662, 9805126, 15372529, 22796475, 25780254, 15922184) with all variants demonstrated or expected to lead to the expression of an altered protein, consistent with a dominant-negative impact on the triple chains collagen molecule. For example, three of the reported variants were shown by RT-PCR to cause an in-frame exon skipping. Other reported variants affect the Gly-X-Y triplet of the protein. Several of these variants segregated with disease in 27 additional family members. In summary, COL11A2 is definitely associated with autosomal dominant otospondylomegaepiphyseal dysplasia. 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 Hearing Loss Working Group on 12/20/18.
Inheritance Pattern: AR
Disease ID:MONDO:0008975
Submitter: ClinGen
The COL11A2 gene has been reported in association with multiple conditions and inheritance patterns. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in variant type, inheritance pattern, and phenotype within reported COL11A2 cases. Therefore we have split curations by inheritance pattern and again by nonsyndromic hearing loss and otospondylomegaepiphyseal dysplasia and assessed separately. This assessment focuses on its association to autosomal recessive otospondylomegaepiphyseal dysplasia. The COL11A2 gene was first associated with autosomal recessive otospondylomegaepiphyseal dysplasia in humans as early as 1995 (Vikkula et al.). At least 8 variants in 8 probands (missense, nonsense, frameshift) have been reported in humans (PMIDs: 7859284, 16637051, 15558753, 21204229, 21208667, 10677296) with all variants demonstrated or expected to lead to the expression of an altered protein, consistent with a dominant-negative impact on the triple chain collagen molecule. For example, most reported variants affect the Gly-X-Y triplet of the protein. Several of these variants segregated with disease in 10 additional family members. More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The gene-disease association is supported by a homozygous mouse model (Li et al. 2001). In summary, COL11A2 is definitively associated with autosomal recessive otospondylomegaepiphyseal dysplasia. This classification was approved by the ClinGen Hearing Loss Working Group on 12/20/2018.
Inheritance Pattern: AR
Disease ID:MONDO:0019497
Submitter: ClinGen
The COL11A2 gene has been reported in relationship with multiple conditions and inheritance patterns. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in variant type, inheritance pattern, and phenotype within reported COL11A2 cases. Therefore we have split curations by inheritance pattern and again by nonsyndromic hearing loss and Stickler syndrome and assessed separately. This assessment focuses on its relationship to autosomal recessive nonsyndromic hearing loss. The COL11A2 gene was first associated with this disease in humans as early as 2005 (Chen et al.). At least 4 missense variants and 2 null variants in 5 probands have been reported in humans (PMIDs: 25633957, 16033917, MORL unpublished data). Variants in this gene segregated with disease in 10 additional family members. This gene-disease relationship is supported by relevant expression and functional studies. 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 gene-disease pair was originally evaluated by the Hearing Loss GCEP on 12/20/2018. It was re-evaluated on 11/15/2023. As a result of this reevaluation, the classification did not change. However additional genetic evidence (PMID: 33597575) and experimental evidence in the form of a mouse model (PMID:10581026) have been included with scoring adjusted to the current Gene Clinical Validity SOP Version 9.
Inheritance Pattern: AD
Disease ID:MONDO:0008490
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: ClinGen
The *COL11A2* gene was first associated with autosomal dominant nonsyndromic hearing loss in humans as early as 1999 (McGuirt et al., 1999, PMID:10581026). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in variant type, inheritance pattern, and phenotype within reported *COL11A2* cases. Therefore we have split curations by inheritance pattern for nonsyndromic hearing loss and otospondylomegaepiphyseal dysplasia and assessed them separately. This curation focuses on its relationship with autosomal dominant nonsyndromic hearing loss. At least 18 unique variants (missense, nonsense, synonymous, splice-site, and deletion) in 18 probands have been reported in humans (PMIDs:10581026, 23990876, 23967202, 26969326, 27911912, 27610647, 31152317, 33297549, 31045651, 33229591, 33597575, 36515421, 36703223, 36597107, doi:10.1007/s13258-016-0440-4). Variants in this gene segregated with disease in 41 additional family members (PMID:10581026). This gene-disease relationship is also supported by an expression study (PMID:15141750). In summary, there is definitive evidence to support the relationship between *COL11A2* and autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 12/20/2018. It was re-evaluated on 11/15/2023. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new genetic evidence (PMIDs:23990876, 23967202, 26969326, 27911912, 27610647, 31152317, 33297549, 31045651, 33229591, 33597575, 36515421, 36703223, 36597107, doi:10.1007/s13258-016-0440-4) although no new experimental evidence was included. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 11/15/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0011159
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012333
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Ophthalmologic
Intervention: Audiologic/Otolaryngologic; Ophthalmologic
Rationale: Though the condition may be recognizable, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Avoidance of risk factors related to ocular manifestations (eg, contact sports) is indicated
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL11A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_080680.3. 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 | 32 | 628 | 5 | 665 | ||
| missense | 4 | 32 | 923 | 295 | 13 | 1267 |
| nonsense | 30 | 23 | 2 | 55 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 59 | 23 | 5 | 87 | ||
| splice donor/acceptor (+/-2bp) | 7 | 52 | 10 | 69 | ||
| Total | 100 | 131 | 973 | 923 | 18 | 2145 |
Highest pathogenic variant AF is 0.0000888372
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_542411.2 | 66 | MANE Select | |
| Ensembl | ENSP00000339915.2 | 66 | MANE Select | |
| RefSeq | NP_001157243.1 | 5 | Standard | |
| RefSeq | NP_001411037.1 | 65 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col11a2 | Danio rerio | Structure: chondrocyte Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein digestion and absorption - Homo sapiens (human)
- Neural Crest Differentiation
- Focal Adhesion
- Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
- Collagen chain trimerization
Biological Process
- skeletal system development
- sensory perception of sound
- extracellular matrix organization
- collagen fibril organization
- cartilage development
Molecular Function
- extracellular matrix structural constituent
- protein binding
- extracellular matrix structural constituent conferring tensile strength
- protein binding, bridging
- metal ion binding
Cellular Component
- extracellular region
- collagen trimer
- collagen type XI trimer
- extracellular space
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374708
- Coding exons
- 64
- Length
- 29819
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 43
- Defined
- 125748
- p
- 0.000171
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.37 | 755 | 962 | 0.785 | 0.0000585 | 10101 |
| Missense (PolyPhen) | 146 | 262.82 | 0.55552 | 2603 | ||
| Synonymous | 1.01 | 333 | 357 | 0.932 | 0.0000213 | 3689 |
| Loss of Function | 7.73 | 25 | 114 | 0.219 | 0.00000728 | 1238 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00028 | 0.00027 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00024 | 0.00024 | rare |
| South Asian | 0.000099 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.;
- Disease
- DISEASE: Otospondylomegaepiphyseal dysplasia, autosomal dominant (OSMEDA) [MIM:184840]: An autosomal dominant form of otospondylomegaepiphyseal dysplasia, a disorder characterized by sensorineural deafness, enlarged epiphyses, mild platyspondyly, and disproportionate shortness of the limbs. Total body length is normal. Typical facial features are mid-face hypoplasia, short upturned nose and depressed nasal bridge. Most patients have Pierre Robin sequence including an opening in the roof of the mouth (cleft palate) and a small lower jaw (micrognathia). Ocular symptoms are absent. Some patients have early-onset osteoarthritis. {ECO:0000269|PubMed:7859284, ECO:0000269|PubMed:9506662, ECO:0000269|PubMed:9805126}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Otospondylomegaepiphyseal dysplasia, autosomal recessive (OSMEDB) [MIM:215150]: An autosomal recessive form of otospondylomegaepiphyseal dysplasia, a disorder characterized by sensorineural deafness, enlarged epiphyses, mild platyspondyly, and disproportionate shortness of the limbs. Total body length is normal. Typical facial features are mid-face hypoplasia, short upturned nose and depressed nasal bridge. Most patients have Pierre Robin sequence including an opening in the roof of the mouth (cleft palate) and a small lower jaw (micrognathia). Ocular symptoms are absent. Some patients have early-onset osteoarthritis. {ECO:0000269|PubMed:10677296, ECO:0000269|PubMed:7859284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 13 (DFNA13) [MIM:601868]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:10581026}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 53 (DFNB53) [MIM:609706]: A form of non-syndromic sensorineural deafness characterized by prelingual, profound, non-progressive hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:16033917, ECO:0000269|PubMed:25633957}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fibrochondrogenesis 2 (FBCG2) [MIM:614524]: A severe skeletal dysplasia characterized by a flat midface, short long bones, short ribs with broad metaphyses, and vertebral bodies that show distinctive hypoplastic posterior ends and rounded anterior ends, giving the vertebral bodies a pinched appearance on lateral radiographic views. The chest is small, causing perinatal respiratory problems which usually, but not always, result in lethality. Affected individuals who survive the neonatal period have high myopia, mild to moderate hearing loss, and severe skeletal dysplasia. {ECO:0000269|PubMed:22246659}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0206
- RVIS EVS
- -1.05
- RVIS percentile EVS
- 7.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.427
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | Medium |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |