EFEMP1
protein-codingEGF containing fibulin extracellular matrix protein 1, the group of Fibulins
Gene summary
This gene encodes a member of the fibulin family of extracellular matrix glycoproteins. Like all members of this family, the encoded protein contains tandemly repeated epidermal growth factor-like repeats followed by a C-terminus fibulin-type domain. This gene is upregulated in malignant gliomas and may play a role in the aggressive nature of these tumors. Mutations in this gene are associated with Doyne honeycomb retinal dystrophy. Alternatively spliced transcript variants that encode the same protein have been described.[provided by RefSeq, Nov 2009]
- DHRD
- FBNL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~58.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0016175
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0958335
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: ClinGen
EFEMP1 was first reported in relation to autosomal dominant Malattia Leventinese and Doyne Honeycomb retinal dystrophy in 1999 (Stone et al., PMID: 10369267). Doyne honeycomb retinal dystrophy is characterized by drusen deposits at the level of the Bruck membrane in the macular and around the edge of the optic nerve head. Malattia Leventinese is characterized by small discrete drusen radiate into the peripheral retina, with the later development of confluent soft drusen in the macular. Only one missense pathogenic variant (p.Arg345Trp) is included in this curation, and it has been consistently described in many studies (PMID: 17666404, 11384588, 11389162, 30541486, 22031286, 12242346, 10369267, 17664227). This variant was found to segregate in two families (LOD: 3.91 in PMID: 17666404; LOD=1.2 in PMID: 11384588). Functional studies showed that wildtype EFEMP1 is a secreted protein, whereas mutant EFEMPT1 is misfolded, secreted inefficiently, and retained within cells (PMID: 12242346). In-vivo studies demonstrated that EFEMP1-knockin mice deposit material that resembled basal deposits in patients with macular dystrophy (PMID: 17666404, 17664227). In summary, EFEMP1 is definitively associated with autosomal dominant . This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0958335
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005338
Submitter: ClinGen
*EFEMP1* has been a candidate gene for glaucoma since its identification as an extracellular matrix gene regulated at the expression level by TGFβ2 in trabecular meshwork cells (PMID: 19450457). It was subsequently identified in a genome-wide association screen as a locus associated with optic disc cup area (PMID: 25631615). Variants in *EFEMP1* were first reported in relation to open-angle glaucoma in 2015, with the publication of a family with multiple affected members showing onset after age 35 years (Mackay et al., PMID: 26162006). Subsequent publications have established that affected individuals may be diagnosed with open-angle glaucoma either during childhood (PMID: 34923728, PMID: 39264138) or in adulthood, and present with ocular hypertension, optic nerve abnormalities including increased vertical cup-to-disc ratio, reduced visual acuity, and/or peripheral visual field constriction. Publications have also linked monoallelic *EFEMP1* variants to the progressive retinal condition Doyne honeycomb degeneration of retina (also known as malattia leventinese, PMID: 10369267). Biallelic *EFEMP1* variants have also been linked to the connective tissue disorder cutis laxa type 1D (PMID: 31792352). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, cases of open-angle glaucoma were found to have a molecular mechanism (monoallelic missense or stop-loss variants with enhanced intracellular or endoplasmic reticulum retention) and mode of inheritance (autosomal dominant) that were distinguishable from the biallelic loss-of-function mechanism of autosomal recessive cutis laxa type 1D. Doyne honeycomb degeneration of retina shares the autosomal dominant mode of inheritance and is also characterized by aberrant intracellular accumulation of EFEMP1 protein in the endoplasmic reticulum (PMID: 34923728), however, it has so far been associated with one particular *EFEMP1* variant (encoding p.Arg345Trp) and has a very distinct phenotype. While one study has found open-angle glaucoma in an affected individual who also shows severe retinal abnormalities (PMID: 39264138), the phenotype is not a sufficiently clear match for Doyne honeycomb degeneration of retina to conclude that the two conditions are part of the same spectrum of disease. Therefore, cases of open-angle glaucoma caused by monoallelic *EFEMP1* variants have been split for curation under a separate disease entity referred to as EFEMP1-related open-angle glaucoma. Eight suspected disease-causing variants in *EFEMP1* have been scored as part of this curation (five missense and three stop-loss). These variants have been collectively reported in nine probands in six publications (PMID: 26162006, PMID: 34923728, PMID: 32476818, PMID: 35946471, PMID: 38083999, PMID: 39264138). All nine probands were heterozygous for their respective variants. Some of these variants have been shown to accumulate intracellularly and/or in the endoplasmic reticulum, and two have been shown to cause disease in animal intravitreal injection models relative to a wild-type control (PMID: 38083999, PMID: 38467175). The mechanism of pathogenicity appears to be monoallelic disruption of EFEMP1 protein localization, possibly leading to loss of retinal ganglion cells (PMID: 38083999). This gene-disease association is also supported by expression profiling indicating that *EFEMP1* has an expression pattern similar to other genes associated with early onset glaucoma, with high levels in beam cells, trabecular meshwork-related cells, and cribiform juxtacanalicular cells (PMID: 34923728). *EFEMP1* encodes a glycoprotein component of the extracellular matrix, and functions to contribute to the integrity of basement membrane zones and to anchor other extracellular matrix structures such as elastic fibers to basement membranes. Animal models relevant to open-angle glaucoma are limited to the aforementioned intravitreal injection studies in mice and rats showing progressive increases in intraocular pressure, ganglion cell loss (PMID: 38083999), and increased staining for the extracellular matrix marker fibronectin (PMID: 38467175). In summary, *EFEMP1* has moderate evidence of association with EFEMP1-related open-angle glaucoma. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Moderate classification. Additional genetic evidence from cases with *EFEMP1* variants will be required to reach a more definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on December19th, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0007471
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019572
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020367
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Ophthalmologic
Intervention: Gastrointestinal; Genitourinary
Rationale: Cutis laxa, autosomal recessive, type ID can involve manifestations such as gastrointestinal tract and urinary bladder diverticulae, and awareness may enable early identification and management
Comments: Photodynamic therapy may be beneficial for individuals with Doyne honeycomb degeneration of retina
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EFEMP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001039348.3. 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 | 8 | 80 | 2 | 90 | ||
| missense | 1 | 4 | 193 | 12 | 210 | |
| nonsense | 3 | 4 | 4 | 11 | ||
| start loss | 0 | |||||
| frameshift | 3 | 1 | 1 | 5 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 7 | 9 | 208 | 92 | 2 | 318 |
Highest pathogenic variant AF is 0.000012316771
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001034437.1 | 10 | MANE Select | |
| Ensembl | ENSP00000347596.3 | 10 | MANE Select | |
| RefSeq | NP_001034438.1 | 10 | Standard | |
| Ensembl | ENSP00000378058.2 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Extracellular matrix organization
- Molecules associated with elastic fibres
- Elastic fibre formation
Biological Process
- regulation of transcription, DNA-templated
- epidermal growth factor receptor signaling pathway
- visual perception
- regulation of signaling receptor activity
- peptidyl-tyrosine phosphorylation
Molecular Function
- epidermal growth factor-activated receptor activity
- epidermal growth factor receptor binding
- extracellular matrix structural constituent
- calcium ion binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- extracellular matrix
- collagen-containing extracellular matrix
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394555
- Coding exons
- 10
- Length
- 58173
- Individuals with no LoFs
- 125417
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125418
- p
- 0.00000399
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.82 | 192 | 277 | 0.692 | 0.0000161 | 3241 |
| Missense (PolyPhen) | 51 | 99.814 | 0.51095 | 1148 | ||
| Synonymous | -0.829 | 112 | 101 | 1.10 | 0.00000609 | 926 |
| Loss of Function | 4.99 | 1 | 31.0 | 0.0322 | 0.00000200 | 325 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds EGFR, the EGF receptor, inducing EGFR autophosphorylation and the activation of downstream signaling pathways. May play a role in cell adhesion and migration. May function as a negative regulator of chondrocyte differentiation. In the olfactory epithelium, it may regulate glial cell migration, differentiation and the ability of glial cells to support neuronal neurite outgrowth. {ECO:0000269|PubMed:19804359, ECO:0000269|PubMed:19887559, ECO:0000269|PubMed:20005202}.;
Recessive Scores
- pRec
- 0.235
Intolerance Scores
- LoFtool
- 0.0142
- RVIS EVS
- -0.76
- RVIS percentile EVS
- 13.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.774
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |