C1QTNF5

protein-coding

C1q and TNF related 5, the group of C1q and TNF related

Gene summary

This gene encodes a member of a family of proteins that function as components of basement membranes and may play a role in cell adhesion. Mutations in this gene have been associated with late-onset retinal degeneration. The protein may be encoded by either a bicistronic transcript including sequence from the upstream membrane frizzled-related protein gene (MFRP), or by a monocistronic transcript expressed from an internal promoter. [provided by RefSeq, Jun 2013]

MANE transcript

NM_001278431.2

Inheritance

ClinVar variants

P:7U:136B:75

Top phenotype

Late-onset retinal degeneration

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr11:119,338,942-119,340,940

External References & Databases

Ensembl (ENSG00000223953)

Transcript & Mutation Effects

hg38 • Region Span ~2.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

late-onset retinal degenerationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011579

Submitter: Orphanet

late-onset retinal degenerationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011579

Submitter: Labcorp Genetics (formerly Invitae)

inherited retinal dystrophyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019118

Submitter: ClinGen

*C1QTNF5* was first reported in relation to autosomal dominant retinal degeneration in 2003 (Hayward et al., PMID: 12944416). C1QTNF5-related retinopathy, also referred to in the literature as late-onset retinal degeneration, has symptoms typically appearing in the fifth or sixth decade of life. The first symptom is usually night blindness with punctate yellow-white deposits visible on fundus exam. As the disease progresses, individuals develop severe retinal degeneration in both the central and the peripheral retina as well as choroidal neovascularization, chorioretinal atrophy and sub-RPE deposits. This curation includes six missense variants that have been reported in eighteen probands in seven publications (PMIDs: 12944416, 28939808, 32036094, 23289492, 38129706, 33669876, 38819368). Of note, the c.489C>G (p.Ser163Arg) variant is the most common variant and was shown to be a founder variant that appears to have originated in south-east Scotland (PMID: 12944416). The mechanism of pathogenicity appears to be dominant negative. This gene-disease relationship is also supported by experimental evidence that *C1QTNF5* is expressed in retinal pigment epithelium cells with some specificity, that disease-associated missense variants affect protein expression and secretion, and that mouse models of the disease and RPE cells derived from induced pluripotent stem cells recapitulate the affected patient phenotype (PMIDs: 12944416, 28939808, 32036094, 34887495, 16123441, 36328299, 21349921, 37440053, 26513502). In summary, there is definitive evidence supporting the relationship between *C1QTNF5* and C1QTNF5-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification has been approved by the ClinGen Retina GCEP on September 6th, 2024 (SOP Version 10).

late-onset retinal degenerationDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011579

Submitter: G2P

Clinical Genomic Database (CGD)

Late-onset retinal degenerationAD

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12944416; 22277927; 23289492

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C1QTNF5 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 211

not specifiedTotal: 27

C1QTNF5-related disorderTotal: 23

Late-onset retinal degenerationTotal: 22

Inborn genetic diseasesTotal: 21

Isolated microphthalmia 5Total: 16

Retinal dystrophyTotal: 11

C1QTNF5-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278431.2. 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			3 clinvar	70 clinvar		73
missense	1 clinvar	6 clinvar	125 clinvar	3 clinvar		135
nonsense						0
start loss						0
frameshift			7 clinvar	2 clinvar		9
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	6	136	75	0	218

Highest pathogenic variant AF is 0.000008212642

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001278431.2	RefSeq	NP_001265360.1	2	MANE Select
ENST00000528368.3	Ensembl	ENSP00000431140.1	2	MANE Select
NM_015645.5	RefSeq	NP_056460.1	2	Standard
ENST00000530681.2	Ensembl	ENSP00000456533.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein secretion
inner ear development
protein trimerization

Molecular Function

identical protein binding

Cellular Component

collagen trimer
extracellular space
plasma membrane
bicellular tight junction
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000445041
Coding exons: 2
Length: 7732
Individuals with no LoFs: 124239
Homozygous LoFs: 0
Heterozygous LoFs: 179
Defined: 124418
p: 0.000720

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.16	96	134	0.718	0.00000664	1524
Missense (PolyPhen)		37	64.153	0.57675		753
Synonymous	0.374	59	62.8	0.940	0.00000357	545
Loss of Function	2.26	0	5.95	0.00	2.55e-7	69

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0044	0.0044	notable
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00060	0.00060	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00059	0.00058	rare
South Asian	0.00033	0.00033	rare
Other	0.00099	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Late-onset retinal degeneration (LORD) [MIM:605670]: Autosomal dominant disorder characterized by onset in the fifth to sixth decade with night blindness and punctate yellow-white deposits in the retinal fundus, progressing to severe central and peripheral degeneration, with choroidal neovascularization and chorioretinal atrophy. {ECO:0000269|PubMed:12944416, ECO:0000269|PubMed:22892318}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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