COL4A3

protein-coding

collagen type IV alpha 3 chain, the group of Collagens

Gene summary

Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

MANE transcript

NM_000091.5

Inheritance

AD, SD, AR

ClinVar variants

P:1114U:765B:755

Top phenotype

Alport syndrome 3A, autosomal dominant; Alport syndrome 3B, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr2:227,164,624-227,314,792

External References & Databases

Ensembl (ENSG00000169031)

Transcript & Mutation Effects

hg38 • Region Span ~150.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Alport syndrome 3b, autosomal recessiveDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0957811

Submitter: G2P

Alport syndromeDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0018965

Submitter: Natera

autosomal recessive Alport syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008762

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.

autosomal dominant Alport syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007086

Submitter: Orphanet

autosomal recessive Alport syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Myriad Women's Health

Alport syndromeDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0018965

Submitter: ClinGen

The *COL4A3* gene is located on chromosome 2 at q36.3 and encodes the protein collagen alpha-3(IV) chain. *COL4A3* was first reported in relation to autosomal recessive Alport Syndrome in 1994 (Mochizuki et al., PMID: 7987396). Alport syndrome is characterized by hearing loss, anterior lenticonus, and glomerular basement membrane defects that may progress to end-stage kidney disease. Patients often present with hematuria and worsening proteinuria. Kidney biopsy may identify focal segmental glomerulosclerosis and thin glomerular basement membranes with abnormal ultrastructure. Autosomal dominant inheritance has also been reported, leading to an isolated renal phenotype of hematuria, with or without structural changes and progressive disease course. Case reports of digenic inheritance with *COL4A4* or *COL4A5* variants also exist. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism between the reported disease entities and noted that affected families show phenotypic variability with variable expressivity. Therefore, the following disease entities have been lumped into a single disease entity, Alport syndrome 3, autosomal dominant (OMIM:104200), Alport syndrome 2, autosomal recessive (OMIM:203780) and Hematuria, benign familial (OMIM:141200). The preferred disease name suggested for this grouping of disorders is ‘Alport Spectrum - *COL4A3*’. Twenty three variants (missense, nonsense, frameshift) that have been reported in 17 probands in 4 publications (PMID: 33532864, PMID: 33838161, PMID: 26346198, PMID: 7987396 ) 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 animal models (PMID: 32743880, PMID: 16775036, PMID: 33718859, PMID: 14507670), expression studies (PMID: 33718859, PMID: 28495876), and *in vitro* functional assays (PMID: 24262798, PMID: 14633121). In summary, *COL4A3* is definitively associated with Alport Spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

autosomal recessive Alport syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Genomics England PanelApp

autosomal dominant Alport syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007086

Submitter: Genomics England PanelApp

hematuria, benign familial, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007709

Submitter: Genomics England PanelApp

autosomal recessive Alport syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Labcorp Genetics (formerly Invitae)

hematuria, benign familial, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007709

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive Alport syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Orphanet

Alport syndrome 3b, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957811

Submitter: G2P

Clinical Genomic Database (CGD)

Alport syndrome 3A, autosomal dominant; Alport syndrome 3B, autosomal recessiveAD/AR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic; Renal

Intervention: Ophthalmologic; Renal

Rationale: In Alport syndrome, medical treatment related to renal sequelae (eg, with ACE inhibitors, ARBs) may be beneficial related to delaying renal failure, as well as with overall life expectancy, though dialysis/renal transplantation may be required; Corneal protection may be beneficial in individuals with recurrent corneal erosions

Refs: 7033680; 7987301; 8196274; 7987396; 7783412; 7783419; 9195222; 9269635; 11961012; 11134255; 20301386; 22166847; 22237748; 22811928; 22997344; 23927549

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL4A3 variants in ClinVar

35 Conditions Cataloged

not providedTotal: 2344

Autosomal dominant Alport syndromeTotal: 841

Alport syndromeTotal: 734

Alport syndrome 3b, autosomal recessiveTotal: 536

Hematuria, benign familial, 2Total: 473

Autosomal recessive Alport syndromeTotal: 395

not specifiedTotal: 305

COL4A3-related disorderTotal: 284

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000091.5. 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	2 clinvar	2 clinvar	39 clinvar	649 clinvar	6 clinvar	698
missense	28 clinvar	499 clinvar	705 clinvar	95 clinvar	5 clinvar	1332
nonsense	55 clinvar	76 clinvar	1 clinvar			132
start loss		4 clinvar				4
frameshift	137 clinvar	134 clinvar	2 clinvar			273
splice donor/acceptor (+/-2bp)	29 clinvar	148 clinvar	18 clinvar			195
Total	251	863	765	744	11	2634

Highest pathogenic variant AF is 0.00059048994

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000091.5	RefSeq	NP_000082.2	52	MANE Select
ENST00000396578.8	Ensembl	ENSP00000379823.3	52	MANE Select
ENST00000304990.8	Ensembl	ENSP00000302781.8	5	Standard
ENST00000469504.2	Ensembl	ENSP00000493493.1	4	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)
Relaxin signaling pathway - Homo sapiens (human)
AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)

Biological Process

activation of cysteine-type endopeptidase activity involved in apoptotic process
cell adhesion
cell surface receptor signaling pathway
sensory perception of sound
blood circulation

Molecular Function

integrin binding
structural molecule activity
extracellular matrix structural constituent
protein binding
metalloendopeptidase inhibitor activity

Cellular Component

extracellular region
collagen type IV trimer
basement membrane
extracellular space
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396578
Coding exons: 52
Length: 150228
Individuals with no LoFs: 124648
Homozygous LoFs: 0
Heterozygous LoFs: 146
Defined: 124794
p: 0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.99	763	935	0.816	0.0000484	10352
Missense (PolyPhen)		144	201.02	0.71635		2111
Synonymous	0.537	315	327	0.962	0.0000186	3697
Loss of Function	5.45	38	95.4	0.398	0.00000489	1208

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00058	0.00058	rare
Latino/Admixed American	0.00099	0.00099	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00039	0.00039	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00053	0.00053	rare
South Asian	0.00076	0.00075	rare
Other	0.00083	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.;
Disease: DISEASE: Note=Autoantibodies against the NC1 domain of alpha 3(IV) are found in Goodpasture syndrome, an autoimmune disease of lung and kidney.; DISEASE: Alport syndrome, autosomal recessive (APSAR) [MIM:203780]: A syndrome characterized by progressive glomerulonephritis, glomerular basement membrane defects, renal failure, sensorineural deafness and specific eye abnormalities (lenticonous and macular flecks). The disorder shows considerable heterogeneity in that families differ in the age of end-stage renal disease and the occurrence of deafness. {ECO:0000269|PubMed:11134255, ECO:0000269|PubMed:15954103, ECO:0000269|PubMed:29946535}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hematuria, benign familial (BFH) [MIM:141200]: An autosomal dominant condition characterized by non-progressive isolated microscopic hematuria that does not result in renal failure. It is characterized pathologically by thinning of the glomerular basement membrane. {ECO:0000269|PubMed:11961012}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alport syndrome, autosomal dominant (APSAD) [MIM:104200]: A syndrome characterized by progressive glomerulonephritis, glomerular basement membrane defects, renal failure, sensorineural deafness and specific eye abnormalities (lenticonous and macular flecks). The disorder shows considerable heterogeneity in that families differ in the age of end-stage renal disease and the occurrence of deafness. {ECO:0000269|PubMed:11044206, ECO:0000269|PubMed:11134255}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.340

Intolerance Scores

LoFtool: 0.0989
RVIS EVS: 1.35
RVIS percentile EVS: 94.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.461

Gene Damage Prediction

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