EFEMP1

Chr 2ARAD

EGF-like fibulin extracellular matrix protein 1

Also known as: ARCL1D, DHRD, DRAD, FBLN3, FBNL, FIBL-3, GLC1H, MLVT

NCBI Gene: 2202 ENSG00000115380 UniProt: Q12805 OMIM: 601548

This gene encodes fibulin-4, an extracellular matrix glycoprotein that binds the EGF receptor and regulates cell adhesion, migration, and glial cell functions in neural development. Mutations cause Doyne honeycomb retinal dystrophy and open-angle glaucoma (autosomal dominant) as well as autosomal recessive cutis laxa with connective tissue abnormalities. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.153 OMIM phenotypes

Clinical Summary— EFEMP1

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Gene-Disease Validity (ClinGen)

Doyne honeycomb retinal dystrophy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 8 VUS of 36 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 4.99

OE 0.03 (0.01–0.15)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.82Z-score

OE missense 0.69 (0.61–0.78)

192 obs / 277.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.15)

0≤0.351.4

Missense OE?0.69 (0.61–0.78)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 31.0Missense obs/exp: 192 / 277.5Syn Z: -0.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEFEMP1-related Doyne honeycomb degeneration of retinaOTHERAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.4776th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.15

GOF1 literature citation

Literature Evidence

GOFA recurrent gain-of-function variant (p.(Arg345Trp)) in EFEMP1 has previously been associated with Doyne honeycomb retinal dystrophy.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 33807164 ↗

ClinVar Variant Classifications

36 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS8

Likely Benign4

Benign20

Conflicting3

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	0	2	5	1	8
Likely Benign	0	0	2	2	4
Benign	0	1	16	3	20
Conflicting	—				3
Total	0	4	23	6	36

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

2 pathogenic / likely-pathogenic (of 4) ClinVar copy-number / structural variants overlap EFEMP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →