COL9A3

protein-coding

collagen type IX alpha 3 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. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3. [provided by RefSeq, Jan 2010]

MANE transcript

NM_001853.4

Inheritance

AR, AD

ClinVar variants

P:66U:722B:356

Top phenotype

Stickler syndrome, type VI

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr20:62,816,244-62,841,159

External References & Databases

Ensembl (ENSG00000092758)

Transcript & Mutation Effects

hg38 • Region Span ~24.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Stickler syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019354

Submitter: ClinGen

*COL9A3* was reported in relation to autosomal recessive Stickler syndrome in 2014 (Faletra et al., 24273071). Of note, this gene has also been implicated in multiple epiphyseal dysplasia, susceptibility to intervertebral disc disease, and non-syndromic hearing loss. These have been or will be assessed separately. At least eight unique nonsense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least seven probands in five publications (PMID: 24273071, 30450842,31090205,33570243, 35241111). This gene-disease association is supported by expression studies and animal models(PMIDs: 1844825,15802199, 20686772). In summary, there is definitive evidence to support this gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss Working group on September 18th 2019 (SOP Version 7). It was reevaluated on December 21st 2022. As a result of this reevaluation, the classification did change from moderate to definitive due and new case level evidence was reviewed and added (SOP Version 9)

epiphyseal dysplasia, multiple, 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010964

Submitter: Illumina

Stickler syndrome, type 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0031047

Submitter: Ambry Genetics

epiphyseal dysplasia, multiple, 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010964

Submitter: G2P

autosomal recessive Stickler syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016647

Submitter: Orphanet

epiphyseal dysplasia, multiple, 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010964

Submitter: Ambry Genetics

multiple epiphyseal dysplasia due to collagen 9 anomalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015627

Submitter: Orphanet

Stickler syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019354

Submitter: Ambry Genetics

Stickler syndrome, type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031047

Submitter: Labcorp Genetics (formerly Invitae)

epiphyseal dysplasia, multiple, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010964

Submitter: Labcorp Genetics (formerly Invitae)

Stickler syndrome, type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031047

Submitter: G2P

Stickler syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019354

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Stickler syndrome, type VIAR

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: 10090888; 10655510; 15551337; 20301302; 24273071; 30450842; 31090205; 33570243; 35241111

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL9A3 variants in ClinVar

20 Conditions Cataloged

not providedTotal: 1625

not specifiedTotal: 305

Inborn genetic diseasesTotal: 158

COL9A3-related disorderTotal: 130

Epiphyseal dysplasia, multiple, 3Total: 55

Intervertebral disc disorderTotal: 28

Connective tissue disorderTotal: 25

Stickler syndrome, type 6Total: 24

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001853.4. 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			21 clinvar	301 clinvar	1 clinvar	323
missense		1 clinvar	650 clinvar	54 clinvar		705
nonsense	10 clinvar	7 clinvar	5 clinvar			22
start loss		2 clinvar	1 clinvar			3
frameshift	17 clinvar	16 clinvar	10 clinvar			43
splice donor/acceptor (+/-2bp)	4 clinvar	9 clinvar	35 clinvar			48
Total	31	35	722	355	1	1144

Highest pathogenic variant AF is 0.000014893622

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001853.4	RefSeq	NP_001844.3	32	MANE Select
ENST00000649368.1	Ensembl	ENSP00000496793.1	32	MANE Select
ENST00000452372.2	Ensembl	ENSP00000394280.1	12	Standard
ENST00000894732.1	Ensembl	ENSP00000564791.1	31	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

male gonad development
female gonad 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
extracellular space
endoplasmic reticulum lumen
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343916
Coding exons: 32
Length: 24916
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 125748
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.382	471	448	1.05	0.0000293	4119
Missense (PolyPhen)		186	192.84	0.96454		1756
Synonymous	-2.33	231	190	1.21	0.0000144	1544
Loss of Function	3.00	27	49.9	0.541	0.00000303	525

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00036	0.00036	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Structural component of hyaline cartilage and vitreous of the eye.;
Disease: DISEASE: Multiple epiphyseal dysplasia 3 (EDM3) [MIM:600969]: 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:10090888, ECO:0000269|PubMed:25381065}. 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:11308397, ECO:0000269|PubMed:25381065}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Susceptibility to intervertebral disk disease is conferred by variant p.Arg103Trp (PubMed:11308397). {ECO:0000269|PubMed:11308397}.;

Intolerance Scores

LoFtool: 0.0916
RVIS EVS: 0.61
RVIS percentile EVS: 82.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.808

Gene Damage Prediction

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