COL10A1
protein-codingcollagen type X alpha 1 chain, the group of C1q domain containing|Collagens
Gene summary
This gene encodes the alpha chain of type X collagen, a short chain collagen expressed by hypertrophic chondrocytes during endochondral ossification. Unlike type VIII collagen, the other short chain collagen, type X collagen is a homotrimer. Mutations in this gene are associated with Schmid type metaphyseal chondrodysplasia (SMCD) and Japanese type spondylometaphyseal dysplasia (SMD). [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~39.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007983
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007983
Submitter: ClinGen
COL10A1 was first reported in relation to autosomal dominant metaphyseal chondrodysplasia, Schmid type in 1993 (Warman et al., PMID: 8220429). Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature and bowing of the long bones. Radiographic features include widening and irregularity of the growth plates, especially in the distal and proximal femora. Twenty variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 20 probands in 7 publications (PMIDs: 8004099, 8220429, 8304336, 20872587, 25542771, 34367232, 36400164) are included in this curation. Most pathogenic variants cluster in the NC1 domain of the COL10A1, critical to the trimerization of COL10A1. COL10A1 is not a fibrillar collagen, so glycine tripeptide substitutions are not a known mechanism of disease. 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 also supported by an animal model recapitulating the phenotype observed in human patients, expression studies in fibroblasts, and biochemical function supporting the role of COL10A1 in the calcification and ossification of the growth plate (PMIDs: 30010889, 32913098, 37197316). In summary, there is definitive evidence supporting the relationship between COL10A1 and autosomal dominant metaphyseal chondrodysplasia, Schmid type. 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 Skeletal Disorders GCEP on the meeting date June 24, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0007983
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007983
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007983
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL10A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000493.4. 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 | 3 | 72 | 2 | 77 | ||
| missense | 7 | 24 | 290 | 42 | 5 | 368 |
| nonsense | 11 | 11 | 6 | 1 | 29 | |
| start loss | 1 | 1 | ||||
| frameshift | 13 | 27 | 15 | 3 | 58 | |
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 31 | 62 | 315 | 118 | 8 | 534 |
Highest pathogenic variant AF is 0.0000049576
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000484.2 | 2 | MANE Select | |
| Ensembl | ENSP00000498802.1 | 2 | MANE Select | |
| RefSeq | NP_001411035.1 | 2 | Standard | |
| RefSeq | NP_001411036.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein digestion and absorption - Homo sapiens (human)
- Endochondral Ossification
- Senescence and Autophagy in Cancer
- Assembly of collagen fibrils and other multimeric structures
- Collagen chain trimerization
Biological Process
- skeletal system development
- extracellular matrix organization
Molecular Function
- extracellular matrix structural constituent
- protein binding
- extracellular matrix structural constituent conferring tensile strength
- metal ion binding
Cellular Component
- extracellular region
- collagen trimer
- extracellular space
- endoplasmic reticulum lumen
- extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000327673
- Coding exons
- 2
- Length
- 39825
- Individuals with no LoFs
- 125518
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 230
- Defined
- 125748
- p
- 0.000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.15 | 436 | 374 | 1.17 | 0.0000180 | 4223 |
| Missense (PolyPhen) | 39 | 39.101 | 0.99742 | 536 | ||
| Synonymous | -0.189 | 142 | 139 | 1.02 | 0.00000722 | 1639 |
| Loss of Function | 1.74 | 10 | 17.9 | 0.557 | 0.00000103 | 229 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00050 | 0.00049 | rare |
| Ashkenazi Jewish | 0.012 | 0.012 | notable |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00055 | 0.00055 | rare |
| South Asian | 0.00052 | 0.00052 | rare |
| Other | 0.00098 | 0.00098 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Type X collagen is a product of hypertrophic chondrocytes and has been localized to presumptive mineralization zones of hyaline cartilage.;
- Disease
- DISEASE: Schmid type metaphyseal chondrodysplasia (SMCD) [MIM:156500]: Dominantly inherited disorder of the osseous skeleton. The cardinal features of the phenotype are mild short stature, coxa vara and a waddling gait. Radiography usually shows sclerosis of the ribs, flaring of the metaphyses, and a wide irregular growth plate, especially of the knees. A variant form of SMCD is spondylometaphyseal dysplasia Japanese type. It is characterized by spinal involvement comprising mild platyspondyly, vertebral body abnormalities, and end-plate irregularity. {ECO:0000269|PubMed:15880705, ECO:0000269|PubMed:7607655, ECO:0000269|PubMed:7876225, ECO:0000269|PubMed:8004099, ECO:0000269|PubMed:8304336, ECO:0000269|PubMed:8782043, ECO:0000269|PubMed:9067753, ECO:0000269|PubMed:9852679}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.366
Intolerance Scores
- LoFtool
- 0.164
- RVIS EVS
- -0.02
- RVIS percentile EVS
- 52.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Indispensability pred.
- N
- Indispensability score
- 0.340
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | High | High |