GeneBe

COL3A1

protein-coding

collagen type III alpha 1 chain, the group of Collagens|MicroRNA protein coding host genes

Gene summary

This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

Previous symbols:
  • EDS4A

MANE transcript

NM_000090.4

Inheritance

AD, AR

ClinVar variants

P:938U:1306B:717

Top phenotype

Ehlers-Danlos syndrome, vascular type; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr2:188,974,373-189,012,746

External References & Databases

Ensembl (ENSG00000168542)NCBI Gene (1281)OMIM (120180)HGNC:2201GenCCUniProt (P02461)AlphaFoldClinVar (COL3A1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~38.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ehlers-Danlos syndrome, vascular typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017314

Submitter: ClinGen

The relationship between COL3A1 and Ehlers-Danlos syndrome, vascular type (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of February 25th, 2019. Variants in COL3A1 were first reported in humans with this disease as early as 1988 (Superti-Furga et al., PMID 2834369). At least 600 unique variants are found in the Ehlers Danlos Syndrome Variant Database and ~250 more in ClinVar (Byers, 1999; PMID 20301667). This is a well-known gene-disease relationship and there is a significant amount of case-level, segregation and experimental data in the literature, therefore the maximum points for genetic and experimental evidence has been reached. The mechanism for disease is mainly gain-of-function as most cases result from missense variants leading to the substitution of a crucial glycine in the repetitive Gly-X-Y sequence of the triple helix domain, resulting in only 1 in 8 normal mature collagen homotrimers. About 5% of cases are due to haploinsufficiency and are associated with milder phenotypes (Frank et al., 2015; PMID 25758994). This gene-disease relationship is supported by in vitro assays, expression studies, and animal models. In summary, COL3A1 is definitively associated with autosomal dominant Ehlers Danlos Syndrome, vascular 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 GCEP on February 27, 2019 (SOP Version 6).

Ehlers-Danlos syndrome, vascular typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017314

Submitter: Orphanet

autosomal dominant Ehlers-Danlos syndrome, vascular typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007524

Submitter: G2P

autosomal dominant Ehlers-Danlos syndrome, vascular typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007524

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant Ehlers-Danlos syndrome, vascular typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007524

Submitter: Genomics England PanelApp

polymicrogyria with or without vascular-type Ehlers-Danlos syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032688

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant Ehlers-Danlos syndrome, vascular typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007524

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Ehlers-Danlos syndrome, vascular type; Polymicrogyria with or without vascular-type Ehlers-Danlos syndromeAD/AR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Obstetric

Intervention: Cardiovascular; Obstetric

Rationale: Individuals are at risk for manifestations such as bowel and arterial ruptures, as well as severe pregnancy-related complications in women, and surveillance (eg, arterial screening by CT or MRI) and early recognition may allow precautionary measures prompt recognition and treatment of manifestions, which may reduce morbidity and mortality

Comments: Homozygous variants have been reported; An individual with EDS type III with a COL3A1 variant has been reported

Refs: 7230200; 6129381; 3204406; 3337712; 2321591; 2349939; 2243125; 1496983; 1352273; 1557695; 8317500; 7833919; 8526472; 10051163; 10928897; 10706896; 11577371; 12131463; 12786757; 15007000; 19455184; 20301667; 21637106; 22713205; 23052746; 23688910; 24922459; 25205403; 28258187; 28742248Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL3A1 variants in ClinVar

30 Conditions Cataloged
Ehlers-Danlos syndrome, type 4Total: 2921
Familial thoracic aortic aneurysm and aortic dissectionTotal: 1514
not providedTotal: 828
not specifiedTotal: 428
COL3A1-related disorderTotal: 140
Polymicrogyria with or without vascular-type Ehlers-Danlos syndromeTotal: 138
Ehlers-Danlos syndromeTotal: 57
Cardiovascular phenotypeTotal: 20

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000090.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
23
clinvar
633
clinvar
10
clinvar
 669
missense
219
clinvar
402
clinvar
1255
clinvar
65
clinvar
8
clinvar
 1949
nonsense
28
clinvar
23
clinvar
 51
start loss
2
clinvar
 2
frameshift
71
clinvar
23
clinvar
2
clinvar
1
clinvar
 97
splice donor/acceptor (+/-2bp)
100
clinvar
69
clinvar
24
clinvar
 193
Total4185201306699182961

Highest pathogenic variant AF is 0.0000181977

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000090.4RefSeqNP_000081.251MANE Select
ENST00000304636.9EnsemblENSP00000304408.451MANE Select
ENST00000450867.2EnsemblENSP00000415346.250Standard
ENST00000450867.3EnsemblENSP00000415346.250Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Platelet activation - Homo sapiens (human)
  • Relaxin signaling pathway - Homo sapiens (human)
  • AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
  • Protein digestion and absorption - Homo sapiens (human)
  • Amoebiasis - Homo sapiens (human)

Biological Process

  • skeletal system development
  • cell-matrix adhesion
  • transforming growth factor beta receptor signaling pathway
  • integrin-mediated signaling pathway
  • heart development

Molecular Function

  • protease binding
  • integrin binding
  • extracellular matrix structural constituent
  • protein binding
  • extracellular matrix structural constituent conferring tensile strength

Cellular Component

  • extracellular region
  • collagen type III trimer
  • extracellular space
  • endoplasmic reticulum lumen
  • extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000304636
Coding exons
51
Length
38427
Individuals with no LoFs
125740
Homozygous LoFs
0
Heterozygous LoFs
8
Defined
125748
p
0.0000318
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.095168520.6060.00004579134
Missense (PolyPhen)43102.970.41761999
Synonymous-0.9563002801.070.00001583254
Loss of Function8.59493.70.04270.000005521049

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.000200.00020rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000260.000026rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Collagen type III occurs in most soft connective tissues along with type I collagen. Involved in regulation of cortical development. Is the major ligand of ADGRG1 in the developing brain and binding to ADGRG1 inhibits neuronal migration and activates the RhoA pathway by coupling ADGRG1 to GNA13 and possibly GNA12.;
Disease
DISEASE: Ehlers-Danlos syndrome, vascular type (EDSVASC) [MIM:130050]: A severe form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSVASC is an autosomal dominant disease characterized by joint and dermal manifestations as in other forms of the syndrome, and by proneness to spontaneous rupture of bowel and large arteries. The vascular complications may affect all anatomical areas. {ECO:0000269|PubMed:10706896, ECO:0000269|PubMed:10923041, ECO:0000269|PubMed:11168790, ECO:0000269|PubMed:12694234, ECO:0000269|PubMed:12786757, ECO:0000269|PubMed:1352273, ECO:0000269|PubMed:1357232, ECO:0000269|PubMed:1370809, ECO:0000269|PubMed:1496983, ECO:0000269|PubMed:1895316, ECO:0000269|PubMed:2243125, ECO:0000269|PubMed:2349939, ECO:0000269|PubMed:2492273, ECO:0000269|PubMed:2808425, ECO:0000269|PubMed:7749417, ECO:0000269|PubMed:7833919, ECO:0000269|PubMed:7912131, ECO:0000269|PubMed:8019562, ECO:0000269|PubMed:8098182, ECO:0000269|PubMed:8411057, ECO:0000269|PubMed:8514866, ECO:0000269|PubMed:8664902, ECO:0000269|PubMed:8680408, ECO:0000269|PubMed:8884076, ECO:0000269|PubMed:8990011, ECO:0000269|PubMed:9036918, ECO:0000269|PubMed:9147870, ECO:0000269|PubMed:9452103, ECO:0000269|Ref.46, ECO:0000269|Ref.51}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.878

Intolerance Scores

LoFtool
0.0207
RVIS EVS
-0.23
RVIS percentile EVS
36.34

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.841

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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