EMILIN1

protein-coding

elastin microfibril interfacer 1, the group of EMI domain containing|C1q domain containing

Gene summary

This gene encodes an extracellular matrix glycoprotein that is characterized by an N-terminal microfibril interface domain, a coiled-coiled alpha-helical domain, a collagenous domain and a C-terminal globular C1q domain. The encoded protein associates with elastic fibers at the interface between elastin and microfibrils and may play a role in the development of elastic tissues including large blood vessels, dermis, heart and lung. [provided by RefSeq, Sep 2009]

MANE transcript

NM_007046.4

Inheritance

AR, AD

ClinVar variants

P:7U:207B:30

Top phenotype

Arterial tortuosity-bone fragility syndrome

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr2:27,078,615-27,086,403

External References & Databases

Ensembl (ENSG00000138080)

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

arterial tortuosity-bone fragility syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971179

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, autosomal dominant 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859300

Submitter: Labcorp Genetics (formerly Invitae)

arterial tortuosity-bone fragility syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0971179

Submitter: ClinGen

*EMILIN1* was first reported in relation to autosomal recessive Arterial Tortuosity-Bone Fragility Syndrome in 2022 (Adamo et al., PMID: 36351433). Affected individuals are reported with disease onset in the neonatal period or early childhood. Disease hallmarks include arterial tortuosity and bone fragility which can include multiple fractures. Some patients had additional features including dysmorphic facial features, cutis laxa, joint hypermobility, congenital heart malformations, arterial stenosis, and aortic root dilatation. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in molecular mechanism, inheritance pattern and phenotype between patients with autosomal recessive Arterial Tortuosity-Bone Fragility Syndrome and those reported to have autosomal dominant neuronopathy, distal hereditary motor and/or autosomal dominant *EMILIN1*-related connective tissue disease. Therefore, autosomal recessive Arterial Tortuosity-Bone Fragility Syndrome (ClinGen term “EMILIN1-related arterial tortuosity syndrome”) will be curated separately from autosomal dominant forms of disease reported to be associated with this gene. Seven variants (two nonsense, five frameshift) have been reported in five probands in two publications (PMIDs: 36351433, 40062121) and are included in this curation. The mechanism of pathogenicity is reported to be loss of function. To date, all reported cases in the literature have been male and all variants are reported to result in loss of function of the MANE transcript. There is a second transcript which has not been well characterized and to date, all patients have either one or both loss-of-function variants located upstream of the start site for this transcript. This gene-disease relationship is also supported by experimental evidence including a mouse model, expression studies and functional data (PMIDs: 36351433, 14701737). These studies showed reduced EMILIN1 positive signals from elastic fibers in the skin and elastin core abnormalities. They also showed impaired EFEMP2 deposition and reduced LOX levels and enzyme activity. Knock-out mice recapitulated human phenotypes and had bone, collagen, and elastic fiber abnormalities (PMID:36351433). In summary, there is definitive evidence supporting the relationship between the *EMILIN1* gene and *EMILIN1*-related arterial tortuosity syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on June 6, 2025 (SOP Version 11)

neuronopathy, distal hereditary motor, autosomal dominant 10MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859300

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Arterial tortuosity-bone fragility syndromeAR

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiovascular anomalies, and awareness may allow early diagnosis and management

Refs: 26462740; 31978608; 36351433

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EMILIN1 variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 189

not providedTotal: 31

EMILIN1-related disorderTotal: 21

not specifiedTotal: 6

Familial thoracic aortic aneurysm and aortic dissectionTotal: 5

Arterial tortuosity-bone fragility syndromeTotal: 5

Arterial tortuosityTotal: 5

Neuronopathy, distal hereditary motor, autosomal dominant 10Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007046.4. 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	9 clinvar	2 clinvar	14
missense	1 clinvar		202 clinvar	15 clinvar	4 clinvar	222
nonsense	1 clinvar	1 clinvar	1 clinvar			3
start loss						0
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	2	207	24	6	244

Highest pathogenic variant AF is 0.00004106854

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007046.4	RefSeq	NP_008977.1	8	MANE Select
ENST00000380320.9	Ensembl	ENSP00000369677.4	8	MANE Select
ENST00000433140.1	Ensembl	ENSP00000411201.1	5	Standard
ENST00000865593.1	Ensembl	ENSP00000535652.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
emilin1a	Danio rerio	Structure: thrombocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

emilin1a

Danio rerio

Structure: thrombocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

aortic valve morphogenesis
cell adhesion
cell-matrix adhesion
positive regulation of gene expression
negative regulation of gene expression

Molecular Function

protein binding
extracellular matrix constituent conferring elasticity
identical protein binding
integrin binding involved in cell-matrix adhesion

Cellular Component

extracellular region
collagen trimer
extracellular space
extracellular matrix
integrin alpha4-beta1 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380320
Coding exons: 8
Length: 7837
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.21	526	610	0.862	0.0000389	6307
Missense (PolyPhen)		185	235.83	0.78447		2513
Synonymous	1.12	243	266	0.913	0.0000154	2307
Loss of Function	3.82	11	35.6	0.309	0.00000190	374

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.0016	0.0016	notable
European (Non-Finnish)	0.00018	0.00017	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved not only in the formation of the elastic fiber, but also in the processes that regulate vessel assembly. Has cell adhesive capacity.;

Recessive Scores

pRec: 0.148

Intolerance Scores

RVIS EVS: -0.11
RVIS percentile EVS: 45.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.621

Gene Damage Prediction

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