COL2A1

protein-coding

collagen type II alpha 1 chain, the group of Collagens

Gene summary

This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

SEDC
AOM

MANE transcript

NM_001844.5

Inheritance

AD, AR

ClinVar variants

P:1194U:772B:797

Top phenotype

Stickler syndrome, type I; Czech dysplasia; Otospondylomegaepiphyseal dysplasia; Epiphyseal dysplasia, multiple, with myopia and deafness

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr12:47,972,967-48,004,554

External References & Databases

Ensembl (ENSG00000139219)

Transcript & Mutation Effects

hg38 • Region Span ~31.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Stickler syndrome, type I, nonsyndromic ocularSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012287

Submitter: Labcorp Genetics (formerly Invitae)

vitreoretinopathy with phalangeal epiphyseal dysplasiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0031001

Submitter: Labcorp Genetics (formerly Invitae)

achondrogenesis type IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008702

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepiphyseal dysplasia with metatarsal shorteningSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012206

Submitter: Orphanet

spondyloepimetaphyseal dysplasia, Strudwick typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008476

Submitter: Orphanet

spondyloepiphyseal dysplasia congenitaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008471

Submitter: Orphanet

hypochondrogenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019669

Submitter: Orphanet

multiple epiphyseal dysplasia, Beighton typeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007562

Submitter: Labcorp Genetics (formerly Invitae)

spondylometaphyseal dysplasia, Schmidt typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008478

Submitter: Orphanet

spondyloepiphyseal dysplasia congenitaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008471

Submitter: Labcorp Genetics (formerly Invitae)

otospondylomegaepiphyseal dysplasia, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044206

Submitter: Labcorp Genetics (formerly Invitae)

otospondylomegaepiphyseal dysplasia, autosomal recessiveLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044206

Submitter: Labcorp Genetics (formerly Invitae)

achondrogenesis type IIDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008702

Submitter: ClinGen

COL2A1 has been described in association with autosomal dominant Achondrogenesis type II, a severe disorder affecting cartilage and bone development. Comstock et al. described Achondrogenesis type II in 2010 as being "characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction". Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL2A1-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. At least 15 unique variants have been identified in patients (PMIDs: 17994563, 7741714, 7829510, 7757081, 10797431, 31392067, 25823796, 31299979). Evidence supporting this gene-disease relationship includes case-level and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, COL2A1 is definitively associated with autosomal dominant Achondrogenesis type II. 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 Skeletal Disorders Gene Curation Expert Panel on 10/5/2020. Gene Clinical Validity Standard Operating Procedures (SOP) - Version 7.

spondyloepiphyseal dysplasia congenitaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008471

Submitter: G2P

COL2A1-related spondyloepiphyseal dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100602

Submitter: ClinGen

*COL2A1* was first reported in relation to autosomal dominant *COL2A1*-related spondyloepiphyseal dysplasia in 1990 (Tiller et al., PMID: 2339128). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, the following disease entities, spondyloepiphyseal dysplasia congenita, spondyloepiphyseal dysplasia with metatarsal shortening (formerly known as Czech dysplasia), and spondyloepiphyseal dysplasia with metaphyseal changes (SEMD Strudwick type, SMD Algerian type, dysspondyloenchondromatosis, and SMD corner fracture type) have been lumped as a single disease entity based on similarities in inheritance pattern, molecular mechanism, and phenotypic variability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, *COL2A1*-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. At least 11 unique missense variants and 1 inframe deletion that have been reported in 16 individuals across 10 publications are included in this curation (PMIDs: 2339128, 8244341, 16957471, 32071555, 7738948, 16755660, 18553548, 12925722, 17163530, 25735649). Variants in this gene are segregated in 34 additional family members (PMIDs: 18553548, 16755660, 16957471, 8244341). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Notably, the c.2965C>T (p.Arg989Cys) variant (legacy name Arg789Cys) in *COL2A1* has been identified repeatedly in patients with spondyloepiphyseal dysplasia congenita. Pathogenicity of this variant is supported by functional evidence and a mouse model (PMIDs: 15522781, 12968670). Another variant, c.823C>T (p.Arg275Cys), has been also reported in multiple probands with *COL2A1*-related SED with metatarsal shortening (PMIDs: 7738948, 8244341, 8877930, 14730409, 15266623, 15593085, 16155195, 16755660, 17726487, 18553548, 19764028, 21990059, 23448908, 23928235, 32071555) indicating a mutational hot spot in the C-propeptide of *COL2A1* specific to SED with metatarsal shortening. This gene-disease relationship is also supported by expression studies, functional assay, and a mouse model (PMIDs: 3033664, 7806485, 15522781, 12968670). In summary, *COL2A1* is definitvely associated with autosomal dominant *COL2A1*-related spondyloepiphyseal 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 Skeletal Disorders Gene Curation Expert Panel on December 6th, 2021 (SOP version 9).

Stickler syndrome type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007160

Submitter: ClinGen

*COL2A1* was first reported in relation to autosomal dominant Stickler syndrome type 1 in 1987 (Francomano et al., PMID: 2896625). Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. Most forms are identifiable by findings in the eye including high myopia, vitreoretinal degeneration, retinal detachment, and cataracts (Baker et al., PMID: 21671392). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, *COL2A1*-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. 10 variants (missense, nonsense, and frameshift) that have been reported in 10 probands in 7 publications (PMIDs: 1677770, 17721977, 26626311, 27408751, 31736238, 8434604, 8737653) 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 association is also supported by experimental evidence (animal models and expression studies) (PMIDs: 12525971, 16546167, 3033664, 7806485). *COL2A1* is expressed throughout the skeletal structure as well as throughout the eye, with expression in the vitreous space and the ganglion cell layer of the retina being most relevant to the most common phenotypes seen in patients. In summary, *COL2A1* is definitively associated with autosomal dominant Stickler syndrome type 1. 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 Skeletal Disorders Gene Curation Expert Panel on 2/7/22 (SOP version 9).

autosomal dominant rhegmatogenous retinal detachmentSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016202

Submitter: Orphanet

spondyloepiphyseal dysplasia, Stanescu typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014701

Submitter: Orphanet

platyspondylic dysplasia, Torrance typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007895

Submitter: ClinGen

COL2A1 has been described in association with Platyspondylic dysplasia-Torrance type (PLSD-T), “a rare skeletal dysplasia characterized by platyspondyly, extremely short limbs, and mild brachydactyly” (Désire et al. 2011). Platyspondylic dysplasia-Torrance type is lethal in the neonatal period (PMID: 14729840). This curation includes patients diagnosed with Platypondylic dysplasia-Luton type, which represents the less severe, non-lethal end of the same spectrum of disease. Causative variants of PLSD-T fall within the C-propeptide region of COL2A1 (PMID: 12961049). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL2A1-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. At least 10 unique variants (missense, nonsense, frameshift etc.) have been reported in patients with PLSD-T. Genetic and experimental evidence, including two mouse models, support this gene-disease relationship. In summary, COL2A1 is definitively associated with autosomal dominant Platyspondylic dysplasia-Torrance 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 Skeletal Disorders Gene Curation Expert Panel on 2/1/21. Gene Clinical Validity Standard Operating Procedures (SOP) - Version 8.

Kniest dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007987

Submitter: ClinGen

COL2A1 has been described in association with autosomal dominant Kniest dysplasia. The condition is characterized by "disproportionate dwarfism, cleft palate, myopia, progressive conductive hearing loss, arthropathy, and scoliosis. Radiographs of patients with Kniest dysplasia exhibit progressive skeletal changes, including splayed epiphyses and metaphyses, platyspondyly, and narrowed joint space" (PMID: 7977371). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL2A1-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. Evidence supporting this gene-disease relationship includes case level and experimental evidence. At least 11 unique variants have been described across numerous publications. Notably, the c.905C>T (p.Ala302Val), a cryptic splice donor site resulting in an in-frame loss of 7 residues, has been identified repeatedly in patients with Kniest dysplasia (PMIDs: 7977371, 25592122, 17347327, 25525159, 8893763). In summary, COL2A1 is definitively associated with Kniest 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 Skeletal Disorders Gene Curation Expert Panel on 9/1/21 (SOP version 8).

Kniest dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007987

Submitter: Orphanet

Legg-Calve-Perthes diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007885

Submitter: Orphanet

platyspondylic dysplasia, Torrance typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007895

Submitter: Orphanet

dysspondyloenchondromatosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019412

Submitter: Orphanet

familial avascular necrosis of femoral headSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012126

Submitter: Orphanet

Stickler syndrome type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007160

Submitter: Orphanet

mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011496

Submitter: Orphanet

achondrogenesis type IISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008702

Submitter: Orphanet

Stickler syndrome type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007160

Submitter: Illumina

dysplasia of the proximal femoral epiphysesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1030002

Submitter: ClinGen

*COL2A1* was first reported in relation to autosomal dominant dysplasia of the proximal femoral epiphyses in 2005 (Liu et al., PMID: 15930420). Dysplasia of the proximal femoral epiphyses is a relatively milder form of the other skeletal disorders associated with *COL2A1*. It is generally characterized by avascular necrosis of the femoral head, cystic changes of the femoral head, and/or sclerosis of the femoral head. Cases include patients diagnosed with multiple epiphyseal dysplasia with severe proximal femoral dysplasia, avascular necrosis of the femoral head (ANFH), Legg-Calvé-Perthes Disease (LCPD), and Namaqualand hip dysplasia (NHD). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, *COL2A1*-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. 9 variants (missense) that have been reported in 14 probands in 12 publications (PMIDs: 15930420, 17394019, 18512791, 20131279, 24949742, 25050885, 25124518, 29750297, 30740902, 32071555, 33404007, 34088323) are included in this curation. The exact mechanism of pathogenicity is currently unknown, although dysplasia of the proximal femoral epiphyses is commonly associated with p.G393S, p.G717S, and p.G1170S. This gene-disease association is also supported by experimental evidence (expression and functional alteration studies) (PMIDs: 3033664, 7806485, 20204389). In summary, there is definitive evidence supporting the relationship between *COL2A1* and dysplasia of the proximal femoral epiphyses. 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 April 4, 2022 (SOP Version 10).

spondyloepiphyseal dysplasia with metatarsal shorteningDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012206

Submitter: Ambry Genetics

spondyloepimetaphyseal dysplasia, Strudwick typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008476

Submitter: G2P

achondrogenesis type IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008702

Submitter: Ambry Genetics

Stickler syndrome type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007160

Submitter: Genomics England PanelApp

spondyloepiphyseal dysplasia with metatarsal shorteningSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012206

Submitter: Labcorp Genetics (formerly Invitae)

Kniest dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007987

Submitter: Labcorp Genetics (formerly Invitae)

Legg-Calve-Perthes diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007885

Submitter: Labcorp Genetics (formerly Invitae)

achondrogenesis type IIDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008702

Submitter: G2P

Kniest dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007987

Submitter: G2P

otospondylomegaepiphyseal dysplasiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008975

Submitter: Ambry Genetics

Stickler syndrome, type I, nonsyndromic ocularDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012287

Submitter: G2P

spondyloperipheral dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010078

Submitter: ClinGen

*COL2A1* was first reported in relation to autosomal dominant spondyloperipheral dysplasia in 1996 (Zabel et al., PMID: 8723097). Spondyloperipheral dysplasia is a disorder that impairs bone growth. This condition is characterized by flattened bones of the spine (platyspondyly) and unusually short fingers and toes (brachydactyly), with the exception of the first (big) toes. Other skeletal abnormalities associated with spondyloperipheral dysplasia include short stature, shortened long bones of the arms and legs, exaggerated curvature of the lower back (lordosis), and an inward- and upward-turning foot (clubfoot). Additionally, some affected individuals have nearsightedness (myopia), hearing loss, and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, *COL2A1*-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. 7 variants (nonsense, frameshift, and canonical splice site) that have been reported in 7 probands in 6 publications (PMIDs: 15316962, 15895462, 17347327, 21356074, 23545312, 25604898) are included in this curation. The Zabel publication includes an additional proband which cannot be scored due to accession errors (PMID: 8723097). 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. *COL2A1* was shown to be normally expressed in the extracellular matrix surrounding chondrocytes, marrow cells, osteoblasts, fibroblasts and some osteocytes, in addition to chondrocytes in otic capsule (PMIDs: 3033664, 7806485). In summary, there is definitive evidence to support the relationship between *COL2A1* and autosomal dominant spondyloperipheral 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 Skeletal Disorders Gene Curation Expert Panel on 10/4/21 (SOP version 9).

mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011496

Submitter: Labcorp Genetics (formerly Invitae)

avascular necrosis of femoral head, primary, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054550

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepiphyseal dysplasia congenitaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008471

Submitter: G2P

spondyloperipheral dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010078

Submitter: Orphanet

Clinical Genomic Database (CGD)

Stickler syndrome, type I; Czech dysplasia; Otospondylomegaepiphyseal dysplasia; Epiphyseal dysplasia, multiple, with myopia and deafnessAD

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; In Avascular necrosis of femoral head, primary, identifying carriers before the onset of clinical symptoms can allow interventions in order to delay disease progression

Comments: The condition can include varying degrees/types of early hearing loss in some conditions, such as Stickler syndrome and Otospondylomegaepiphyseal dysplasia , while in others, such as Czech dysplasia, the hearing loss typically occurs much later

Refs: 14299791; 5582025; 4568361; 4214536; 699354; 514691; 7036745; 6628450; 6496567; 4014370; 3728560; 2572591; 1975693; 2300123; 1677770; 1671807; 1429602; 1444917; 8434604; 8325895; 8317498; 8737653; 7981752; 7700721; 7874117; 7757081; 7550321; 7847372; 8737653; 8723097; 9800905; 10486316; 10406661; 10745044; 10982970; 11812423; 12939326; 12544472; 12884428; 15266623; 15895462; 15316962; 14729840; 15930420; 16189708; 15671297; 15316962; 16088915; 15643621; 17726487; 16752401; 16155195; 17394019; 17437277; 17509551; 17721977; 18553548; 19764028 ; 20131279; 20583175; 20513134; 21671384; 21204228; 20301479; 21924244; 21332586; 20179744; 23653587; 26183434; 26420734

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL2A1 variants in ClinVar

76 Conditions Cataloged

not providedTotal: 3066

COL2A1-related disorderTotal: 518

not specifiedTotal: 463

Stickler syndrome type 1Total: 321

Inborn genetic diseasesTotal: 178

Achondrogenesis type IITotal: 134

Spondyloepiphyseal dysplasia congenitaTotal: 133

Type 2 collagenopathyTotal: 122

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001844.5. 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 clinvar	2 clinvar	20 clinvar	496 clinvar	14 clinvar	533
missense	159 clinvar	384 clinvar	747 clinvar	261 clinvar	26 clinvar	1577
nonsense	86 clinvar	24 clinvar				110
start loss	3 clinvar					3
frameshift	256 clinvar	61 clinvar	3 clinvar			320
splice donor/acceptor (+/-2bp)	98 clinvar	120 clinvar	2 clinvar			220
Total	603	591	772	757	40	2763

Highest pathogenic variant AF is 0.000006601706

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001844.5	RefSeq	NP_001835.3	54	MANE Select
ENST00000380518.8	Ensembl	ENSP00000369889.3	54	MANE Select
NM_033150.3	RefSeq	NP_149162.2	53	Standard
ENST00000337299.7	Ensembl	ENSP00000338213.6	53	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
col2a1a	Danio rerio	Structure: vertebra Quality: fused with abnormal

Gene / Model

Organism

Observed Phenotype

col2a1a

Danio rerio

Structure: vertebra

Quality: fused with

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Protein digestion and absorption - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)

Biological Process

skeletal system development
cartilage condensation
tissue homeostasis
endochondral ossification
chondrocyte differentiation

Molecular Function

extracellular matrix structural constituent
extracellular matrix structural constituent conferring tensile strength
MHC class II protein binding
identical protein binding
proteoglycan binding

Cellular Component

extracellular region
collagen trimer
collagen type II trimer
basement membrane
extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380518
Coding exons: 54
Length: 31522
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.29	604	879	0.687	0.0000538	9191
Missense (PolyPhen)		25	79.73	0.31356		793
Synonymous	-1.67	358	320	1.12	0.0000215	3311
Loss of Function	8.12	6	88.4	0.0679	0.00000493	1026

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces.;
Disease: DISEASE: Spondyloepiphyseal dysplasia congenital type (SEDC) [MIM:183900]: Disorder characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems. {ECO:0000269|PubMed:10678662, ECO:0000269|PubMed:11746045, ECO:0000269|PubMed:2339128, ECO:0000269|PubMed:2543071, ECO:0000269|PubMed:7757086, ECO:0000269|PubMed:8019561, ECO:0000269|PubMed:8325895, ECO:0000269|PubMed:8423604}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondyloepiphyseal dysplasia, Stanescu type (SEDSTN) [MIM:616583]: An autosomal dominant spondyloepiphyseal dysplasia characterized by glycoproteins accumulation in chondrocytes. Clinical features include progressive joint contractures, premature degenerative joint disease particularly in the knee, hip and finger joints, and osseous distention of the metaphyseal ends of the phalanges causing swolling of interphalangeal joints of the hands. Radiological features include generalized platyspondyly, hypoplastic pelvis, epiphyseal flattening with metaphyseal splaying of the long bones, and enlarged phalangeal epimetaphyses of the hands. {ECO:0000269|PubMed:26183434}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondyloepimetaphyseal dysplasia, Strudwick type (SEMDSTWK) [MIM:184250]: A bone disease characterized by disproportionate short stature from birth, with a very short trunk and shortened limbs, and skeletal abnormalities including lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses. A distinctive radiographic feature is irregular sclerotic changes, described as dappled in the metaphyses of the long bones. {ECO:0000269|PubMed:16088915, ECO:0000269|PubMed:7550321, ECO:0000269|Ref.39}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Achondrogenesis 2 (ACG2) [MIM:200610]: An autosomal dominant disease characterized by the absence of ossification in the vertebral column, sacrum and pubic bones. {ECO:0000269|PubMed:10745044, ECO:0000269|PubMed:10797431, ECO:0000269|PubMed:15054848, ECO:0000269|PubMed:17994563, ECO:0000269|PubMed:2572591, ECO:0000269|PubMed:7757081, ECO:0000269|PubMed:7757086, ECO:0000269|PubMed:7829510}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Legg-Calve-Perthes disease (LCPD) [MIM:150600]: Characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone. {ECO:0000269|PubMed:17394019}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Kniest dysplasia (KD) [MIM:156550]: Moderately severe chondrodysplasia phenotype that results from mutations in the COL2A1 gene. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. {ECO:0000269|PubMed:7874117, ECO:0000269|PubMed:8863156}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Avascular necrosis of femoral head, primary, 1 (ANFH1) [MIM:608805]: A disease characterized by mechanical failure of the subchondral bone, and degeneration of the hip joint. It usually leads to destruction of the hip joint in the third to fifth decade of life. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. ANFH1 inheritance is autosomal dominant. {ECO:0000269|PubMed:15930420, ECO:0000269|PubMed:21671384}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteoarthritis with mild chondrodysplasia (OSCDP) [MIM:604864]: Osteoarthritis is a common disease that produces joint pain and stiffness together with radiologic evidence of progressive degeneration of joint cartilage. {ECO:0000269|PubMed:1975693, ECO:0000269|PubMed:1985108, ECO:0000269|PubMed:7757086, ECO:0000269|PubMed:8507190}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Platyspondylic lethal skeletal dysplasia Torrance type (PLSD-T) [MIM:151210]: Platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of chondrodysplasias characterized by severe platyspondyly and limb shortening. PLSD-T is characterized by varying platyspondyly, short ribs with anterior cupping, hypoplasia of the lower ilia with broad ischial and pubic bones, and shortening of the tubular bones with splayed and cupped metaphyses. Histology of the growth plate typically shows focal hypercellularity with slightly enlarged chondrocytes in the resting cartilage and relatively well-preserved columnar formation and ossification at the chondro-osseous junction. PLSD-T is generally a perinatally lethal disease, but a few long-term survivors have been reported. {ECO:0000269|PubMed:10745044, ECO:0000269|PubMed:14729840, ECO:0000269|PubMed:15643621}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple epiphyseal dysplasia with myopia and conductive deafness (EDMMD) [MIM:132450]: A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. EDMMD is an autosomal dominant disorder characterized by epiphyseal dysplasia associated with progressive myopia, retinal thinning, crenated cataracts, conductive deafness. {ECO:0000269|PubMed:9800905}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondyloperipheral dysplasia (SPD) [MIM:271700]: SPD patients manifest short stature, midface hypoplasia, sensorineural hearing loss, spondyloepiphyseal dysplasia, platyspondyly and brachydactyly. {ECO:0000269|PubMed:15316962}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Stickler syndrome 1 (STL1) [MIM:108300]: An autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable. {ECO:0000269|PubMed:11007540, ECO:0000269|PubMed:20513134, ECO:0000269|PubMed:7977371}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Stickler syndrome 1 non-syndromic ocular (STL1O) [MIM:609508]: An autosomal dominant form of Stickler syndrome characterized by the ocular signs typically seen in Stickler syndrome type 1 such as cataract, myopia, retinal detachment. Systemic features of premature osteoarthritis, cleft palate, hearing impairment, and craniofacial abnormalities are either absent or very mild. {ECO:0000269|PubMed:16752401, ECO:0000269|PubMed:17721977, ECO:0000269|PubMed:8317498}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Rhegmatogenous retinal detachment autosomal dominant (DRRD) [MIM:609508]: A eye disease that most frequently results from a break or tear in the retina that allows fluid from the vitreous humor to enter the potential space beneath the retina. It is often associated with pathologic myopia and in most cases leads to visual impairment or blindness if untreated. {ECO:0000269|PubMed:11007540, ECO:0000269|PubMed:15671297}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Czech dysplasia (CZECHD) [MIM:609162]: A skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes. {ECO:0000269|PubMed:18553548, ECO:0000269|PubMed:19764028, ECO:0000269|PubMed:7757086, ECO:0000269|PubMed:8244341}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.927

Intolerance Scores

LoFtool: 0.00641
RVIS EVS: -1.8
RVIS percentile EVS: 2.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.700

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium