COL5A1
protein-codingcollagen type V alpha 1 chain, the group of Collagens
Gene summary
This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~203.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019567
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007522
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007522
Submitter: ClinGen
Classical Ehlers-Danlos syndrome (EDS) was first described as a distinct type of EDS in the 1960s (Beighton, 1968; PMID: 5682651). Childhood bruising is often the first presentation of classical EDS, which is characterized by joint laxity, fragile, hyperextensible skin, poor wound healing, widened, atrophic scars, and other manifestations of connective tissue weakness (reviewed in PMID: 20847697). The relationship of COL5A1 to autosomal dominant Ehlers-Danlos syndrome, classic type was first reported through linkage analysis in 1995 (Loughlin et al., 1995; PMID: 8541855). In 1996, the first variants were identified in patients by Nicholls et al. (PMID: 8950675) and Wenstrup et al. (PMID: 8923000). Over 150 unique variants have been reported in humans (152 Pathogenic or Likely Pathogenic variants are reported in ClinVar), the majority being frameshift, nonsense, and splicing variants resulting in null alleles, but missense and in-frame indel variants have also been reported. The mechanism for disease is primarily haploinsufficiency; the COL5A1 gene encodes the α1 chain of heterotrimeric type V collagen, which comes together with type I collagen to form collagen fibrils, thus COL5A1 haploinsufficiency is a limiting factor for sufficient production of heterotrimers, thereby compromising its regulatory role in fibril assembly (reviewed in PMID: 28192633). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Fifteen unique variants from 15 probands in 6 publications were curated (PMIDs: 9042913, 8950675, 10796876, 18972565, 8923000, 10777716). Variants in this gene segregated with disease in 19 additional family members (PMIDs: 10777716, 8923000, 18972565, 9042913). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by the function of type V collagen in fibril organization (PMID: 2384532), which is consistent with the connective tissue dysfunction associated with EDS. This function is altered in patient cells (PMID: 15095409 and PMID: 14970208), but can be restored by treatment with exogenous type V collagen (PMID: 18305566). Further support is provided by a mouse model, which recapitulates many features of EDS (PMID: 16492673). In summary COL5A1 is definitively associated with autosomal dominant Ehlers-Danlos syndrome, classic 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 General Gene Curation Expert Panel on the meeting date March 24, 2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0000473
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007522
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007522
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0020066
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Dermatologic; Musculoskeletal; Obstetric; Ophthalmologic
Intervention: Cardiovascular; Obstetric
Rationale: Individuals with Ehlers-Danlos syndrome may have aortic root dilatation, but the natural history is unclear, and may not typically progress, though yearly surveillance with echocardiogram when aortic dilatation or mitral valve prolapse is peresent has been recommended; Precautions in pregnancy may be beneficial; Individuals with Fibromuscular dysplasia may have vascular complications, including aneurysms, and early diagnosis may provide early management
Comments: Homozygous variants have been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL5A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000093.5. 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 | 1 | 42 | 830 | 29 | 902 | |
| missense | 8 | 48 | 1011 | 430 | 89 | 1586 |
| nonsense | 57 | 21 | 1 | 79 | ||
| start loss | 3 | 3 | ||||
| frameshift | 138 | 35 | 5 | 178 | ||
| splice donor/acceptor (+/-2bp) | 23 | 55 | 20 | 98 | ||
| Total | 229 | 160 | 1079 | 1260 | 118 | 2846 |
Highest pathogenic variant AF is 0.00004524399
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000084.3 | 66 | MANE Select | |
| Ensembl | ENSP00000360882.3 | 66 | MANE Select | |
| RefSeq | NP_001265003.1 | 66 | Standard | |
| Ensembl | ENSP00000360885.4 | 66 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein digestion and absorption - Homo sapiens (human)
- Allograft Rejection
- miRNA targets in ECM and membrane receptors
- Focal Adhesion
- Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
Biological Process
- blood vessel development
- heart morphogenesis
- cell adhesion
- cell migration
- extracellular matrix organization
Molecular Function
- integrin binding
- extracellular matrix structural constituent
- protein binding
- heparin binding
- extracellular matrix structural constituent conferring tensile strength
Cellular Component
- extracellular region
- collagen type V trimer
- basement membrane
- extracellular space
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371817
- Coding exons
- 66
- Length
- 203067
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125732
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.07 | 937 | 1.13e+3 | 0.827 | 0.0000747 | 11580 |
| Missense (PolyPhen) | 245 | 290.03 | 0.84473 | 2969 | ||
| Synonymous | -1.82 | 526 | 476 | 1.11 | 0.0000387 | 3909 |
| Loss of Function | 9.75 | 2 | 115 | 0.0174 | 0.00000578 | 1322 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Type V collagen is a member of group I collagen (fibrillar forming collagen). It is a minor connective tissue component of nearly ubiquitous distribution. Type V collagen binds to DNA, heparan sulfate, thrombospondin, heparin, and insulin.;
- Disease
- DISEASE: Ehlers-Danlos syndrome, classic type, 1 (EDSCL1) [MIM:130000]: A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are joint hypermobility and dislocation, and fragile, bruisable skin. EDSCL1 inheritance is autosomal dominant. {ECO:0000269|PubMed:10602121, ECO:0000269|PubMed:11992482, ECO:0000269|PubMed:15580559, ECO:0000269|PubMed:18972565, ECO:0000269|PubMed:9042913}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0114
- RVIS EVS
- -3.01
- RVIS percentile EVS
- 0.52
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.817
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |