COL9A2

protein-coding

collagen type IX alpha 2 chain, the group of Collagen proteoglycans|Collagens

Gene summary

This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

Previous symbols:

EDM2

MANE transcript

NM_001852.4

Inheritance

AD, AR

ClinVar variants

P:69U:561B:262

Top phenotype

Stickler syndrome, Type V

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:40,300,489-40,317,813

External References & Databases

Ensembl (ENSG00000049089)

Transcript & Mutation Effects

hg38 • Region Span ~17.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epiphyseal dysplasia, multiple, 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010844

Submitter: G2P

epiphyseal dysplasia, multiple, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010844

Submitter: Labcorp Genetics (formerly Invitae)

Stickler syndrome, type 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013666

Submitter: G2P

Stickler syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019354

Submitter: ClinGen

COL9A2 was first reported in relation to autosomal recessive Stickler syndrome in 2011 (Baker et al., PMID 21671392). At least 1 variant (frameshift) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, experimental data. Variants in this gene have been reported in at least 1 proband with Stickler syndrome in 1 publication (PMID 21671392). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is biallelic loss of function causes the recessive, syndromic form, wheras heterozygous variants have been identified in patients with autosomal dominant epiphyseal dysplasia phenotype. This gene-disease association is supported by several expression studies investigating the collagen IX pathway in cartilage as well as several animal models with Col IX knockout generated by the disruption of Col9a1. Additionally, a canine model supports this association (Suzuki 2005, Goldstein 2010). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Of note, there is no evidence to support an association with heritable thoracic aortic aneurysm and dissection. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, we have split curations for the disease entities, epiphyseal dysplasia. This classification was approved by the ClinGen Hearing Loss Working Group on 2/19/2019 (SOP Version 5).

Stickler syndrome, type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013666

Submitter: Genomics England PanelApp

multiple epiphyseal dysplasia due to collagen 9 anomalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015627

Submitter: Orphanet

Stickler syndrome, type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013666

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive Stickler syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016647

Submitter: Orphanet

Stickler syndrome, type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013666

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Stickler syndrome, Type VAR

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

Refs: 3238439; 8528240; 12244547; 15633184; 20358595; 21671392; 20301479

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL9A2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 1202

not specifiedTotal: 196

Inborn genetic diseasesTotal: 120

COL9A2-related disorderTotal: 94

Epiphyseal dysplasia, multiple, 2Total: 92

Stickler syndrome, type 5Total: 24

Connective tissue disorderTotal: 15

Stickler syndromeTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001852.4. 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	1 clinvar	1 clinvar	17 clinvar	222 clinvar	3 clinvar	244
missense		3 clinvar	509 clinvar	34 clinvar	2 clinvar	548
nonsense	9 clinvar	8 clinvar	4 clinvar	1 clinvar		22
start loss		1 clinvar				1
frameshift	18 clinvar	12 clinvar	3 clinvar			33
splice donor/acceptor (+/-2bp)	3 clinvar	13 clinvar	28 clinvar			44
Total	31	38	561	257	5	892

Highest pathogenic variant AF is 0.000046753063

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001852.4	RefSeq	NP_001843.1	32	MANE Select
ENST00000372748.8	Ensembl	ENSP00000361834.3	32	MANE Select
ENST00000372736.3	Ensembl	ENSP00000361821.3	4	Standard
ENST00000417105.6	Ensembl	ENSP00000388493.2	10	Standard

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
extracellular matrix organization

Molecular Function

extracellular matrix structural constituent
extracellular matrix structural constituent conferring tensile strength

Cellular Component

extracellular region
collagen type IX trimer
basement membrane
extracellular space
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372748
Coding exons: 32
Length: 17330
Individuals with no LoFs: 118207
Homozygous LoFs: 316
Heterozygous LoFs: 7225
Defined: 125748
p: 0.0304

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.34	354	432	0.819	0.0000261	4182
Missense (PolyPhen)		114	157.99	0.72158		1447
Synonymous	0.934	153	168	0.908	0.0000113	1514
Loss of Function	3.61	22	49.4	0.445	0.00000265	541

Population LoF Frequency

Population	CAF	p-value	Status
African	0.10	0.10	notable
Latino/Admixed American	0.070	0.070	notable
Ashkenazi Jewish	0.0012	0.0012	notable
East Asian	0.11	0.11	notable
Finnish	0.012	0.012	notable
European (Non-Finnish)	0.0024	0.0024	notable
South Asian	0.033	0.033	notable
Other	0.019	0.019	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Structural component of hyaline cartilage and vitreous of the eye.;
Disease: DISEASE: Multiple epiphyseal dysplasia 2 (EDM2) [MIM:600204]: A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. {ECO:0000269|PubMed:10364514}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Intervertebral disc disease (IDD) [MIM:603932]: A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. {ECO:0000269|PubMed:10411504}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Stickler syndrome 5 (STL5) [MIM:614284]: An autosomal recessive 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. STL5 is characterized by high myopia, vitreoretinal degeneration, retinal detachment, mild to moderate sensorineural hearing loss, short stature in childhood, and absence of cleft palate and Pierre Robin sequence. {ECO:0000269|PubMed:21671392}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.163

Intolerance Scores

LoFtool: 0.0969
RVIS EVS: 1.69
RVIS percentile EVS: 96.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.636

Gene Damage Prediction

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