EFEMP2

protein-coding

EGF containing fibulin extracellular matrix protein 2, the group of Fibulins

Gene summary

A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

MANE transcript

NM_016938.5

Inheritance

AR, AD

ClinVar variants

P:48U:258B:202

Top phenotype

Cutis laxa, autosomal recessive type IB

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr11:65,866,441-65,873,592

External References & Databases

Ensembl (ENSG00000172638)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lethal arteriopathy syndrome due to fibulin-4 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017818

Submitter: Orphanet

autosomal recessive cutis laxa type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019572

Submitter: Orphanet

cutis laxa, autosomal recessive, type 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013754

Submitter: PanelApp Australia

thoracic aortic aneurysmLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005396

Submitter: Ambry Genetics

cutis laxa, autosomal recessive, type 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013754

Submitter: Genomics England PanelApp

cutis laxa, autosomal recessive, type 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013754

Submitter: ClinGen

*EFEMP2* has been reported in association with autosomal recessive cutis laxa type 1B (ARCL1B) in at least 49 individuals (Loeys B, De Paepe A, Urban Z GeneReviews, 2023). This gene-disease relationship was originally classified as moderate by the HTAAD GCEP in 12/22/2016. Clinical phenotypes of ARCL1B include cutis laxa, arterial tortuosity, aortic aneurysm, diaphragmatic hernia, emphysema, craniofacial features, and musculoskeletal abnormalities. Phenotype severity ranges from embryonic/perinatal lethality to asymptomatic patients with aortic aneurysm found on imaging. Seven variants (missense and frameshift) reported in 6 probands in 6 publications (PMIDs: 22440127, 30140196, 22070778, 28673110, 23532871, 20389311) are included in this curation. The mechanism of pathogenicity is proposed to be loss of function. This gene-disease association is also supported by experimental evidence including protein expression in the aorta (PMID:23715323) and protein interaction with *LOX*, which is also associated with aortic aneurysm (PMID:19855011). Finally, multiple KO mouse models have recapitulated phenotypes of ARCL1B including emphysema, arterial tortuosity, and aortic aneurysm (PMIDs: 16478991, 17293478). In summary, *EFEMP2* is definitively associated with autosomal recessive cutis laxa type 1B and aortic aneurysm. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The evidence summary was updated by the Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease Gene Curation Expert Panel on 8/23/2024.

cutis laxa, autosomal recessive, type 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013754

Submitter: Ambry Genetics

cutis laxa, autosomal recessive, type 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013754

Submitter: Labcorp Genetics (formerly Invitae)

cutis laxa, autosomal recessive, type 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013754

Submitter: G2P

Clinical Genomic Database (CGD)

Cutis laxa, autosomal recessive type IBAR

Manifestation: Cardiovascular; Dermatologic; Musculoskeletal; Pulmonary

Intervention: Cardiovascular

Rationale: Manifestations can include cardiovascular anomalies, including aortic dilatation and aortic aneurysms, and surveillance may allow early detection and management (eg, with beta-blockers and angiotensin-receptor inhibitors), which can decrease morbidity and mortality; Cigarette smoking should be avoided due to risk of exacerbation of pulmonary manifestations (including emphysema)

Refs: 16685658; 17937443; 19664000; 20389311; 21563328; 22440127; 23212998

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EFEMP2 variants in ClinVar

11 Conditions Cataloged

Cutis laxa, autosomal recessive, type 1BTotal: 412

Cardiovascular phenotypeTotal: 336

not providedTotal: 122

not specifiedTotal: 73

EFEMP2-related disorderTotal: 27

Cutis laxa, autosomal recessive, type 1ATotal: 10

Familial thoracic aortic aneurysm and aortic dissectionTotal: 7

Cutis laxaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016938.5. 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			6 clinvar	188 clinvar	3 clinvar	197
missense	7 clinvar	8 clinvar	251 clinvar	11 clinvar		277
nonsense	2 clinvar	4 clinvar				6
start loss						0
frameshift	13 clinvar	3 clinvar	1 clinvar			17
splice donor/acceptor (+/-2bp)	2 clinvar	9 clinvar				11
Total	24	24	258	199	3	508

Highest pathogenic variant AF is 0.000042752996

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016938.5	RefSeq	NP_058634.4	10	MANE Select
ENST00000307998.11	Ensembl	ENSP00000309953.6	10	MANE Select
ENST00000524408.1	Ensembl	ENSP00000432191.1	2	Standard
ENST00000526624.5	Ensembl	ENSP00000435419.1	5	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

elastic fiber assembly

Molecular Function

extracellular matrix structural constituent
calcium ion binding
protein binding

Cellular Component

extracellular region
basement membrane
collagen-containing extracellular matrix
extracellular exosome
extracellular vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307998
Coding exons: 10
Length: 7152
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125746
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.976	236	282	0.836	0.0000203	2896
Missense (PolyPhen)		73	105.53	0.69172		1105
Synonymous	-1.70	142	118	1.20	0.00000913	856
Loss of Function	3.03	8	24.0	0.333	0.00000113	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Cutis laxa, autosomal recessive, 1B (ARCL1B) [MIM:614437]: A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. ARCL1B features include emphysema, lethal pulmonary artery occlusion, aortic aneurysm, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels. {ECO:0000269|PubMed:16685658, ECO:0000269|PubMed:17937443, ECO:0000269|PubMed:19664000}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.125
RVIS EVS: -0.6
RVIS percentile EVS: 18.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.452

Gene Damage Prediction

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