ELN

protein-coding

elastin

Gene summary

This gene encodes a protein that is one of the two components of elastic fibers. Elastic fibers comprise part of the extracellular matrix and confer elasticity to organs and tissues including the heart, skin, lungs, ligaments, and blood vessels. The encoded protein is rich in hydrophobic amino acids such as glycine and proline, which form mobile hydrophobic regions bounded by crosslinks between lysine residues. Degradation products of the encoded protein, known as elastin-derived peptides or elastokines, bind the elastin receptor complex and other receptors and stimulate migration and proliferation of monocytes and skin fibroblasts. Elastokines can also contribute to cancer progression. Deletions and mutations in this gene are associated with supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. [provided by RefSeq, Aug 2017]

MANE transcript

NM_000501.4

Inheritance

ClinVar variants

P:226U:404B:270

Top phenotype

Cutis laxa, autosomal dominant 1; Supravalvular aortic stenosis

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr7:74,027,789-74,069,907

External References & Databases

Ensembl (ENSG00000049540)

Transcript & Mutation Effects

hg38 • Region Span ~42.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cutis laxa, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007411

Submitter: Genomics England PanelApp

cutis laxa, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007411

Submitter: Ambry Genetics

cutis laxa, autosomal dominant 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007411

Submitter: ClinGen

*ELN* encodes the protein elastin, a structural constituent of the extracellular matrix and primary protein determinant of elasticity in tissues and organs including the heart, skin, lungs, ligaments, and blood vessels. Variants in *ELN* have been reported in individuals with the following disease entities: supravalvular (or supravalvar) aortic stenosis (SVAS) and autosomal dominant cutis laxa (ADCL). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability, resulting in our assessment of gene-disease relationship being split into two disease entities; supravalvular aortic stenosis (MONDO:0008504) and autosomal dominant cutis laxa 1 (MONDO:0007411). This split curation focuses on *ELN*-related ADCL. The relationship of *ELN* and SVAS will be assessed separately in the Congenital Heart Disease Gene Curation Expert Panel. *ELN* was reported in relation to ADCL as early as 1998 (Tassabehji et. al. 1998, PMID 9580666). Patients with *ELN*-related cutis laxa present with loose, hyperextensible skin, premature aged appearance, and distinctive facial features (i.e. large ears, convex nasal ridge, long philtrum). Some patients also exhibit symptoms of joint hyperlaxity, inguinal hernia, ptosis, emphysema, and aortic root dilatation or aneurysm. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Numerous *ELN* variants (e.g. intronic, missense, nonsense, frameshift) have been reported in patients with ADCL, the majority of which are heterozygous frameshift variants located within the 3’ region of the elastin gene (PMID: 29501665). Variants in this gene have been reported in at least twenty-two probands, thirteen of whom are *de novo*, in eleven publications (PMID: 9580666, 9873040, 15381555, 16085695, 21309044, 23442826, 24758204, 26121527, 28383366, 36002914, 38445193). Variants in this gene segregated with disease in an autosomal dominant manner in twelve additional family members (PMID: 16085695, 23442826). A subset of ADCL patients exhibiting aortic root dilatation or aneurysm (PMID: 36173875) were reported to be caused by heterozygous frameshift variants located in exons 30 to 34 of *ELN*. Two mutational hotspots, NM_000501.4:c.1973del (published as c.2039delC, c.2158delC, or c.2159delC in exon 30), and NM_000501.4:c.2058del (published as c.2262delA in exon 32) have been repeatedly reported in both familial and sporadic cases of ADCL with varying severity of aortic aneurysm disease including dissection in one patient (PMID: 9873040, 16085695, 23442826). Furthermore, this gene-disease relationship is supported by animal models, expression studies, in vitro functional assays (PMID: 16085695, 20600892, 21309044, 22573328). Expression studies of patient fibroblast cultures show frameshift variants situated within the 3’ end of the ELN gene to produce a stable mutant mRNA isoform via alternate splicing, whereby the C-terminus of tropoelastin is replaced with a missense sequence with read-through into the 3’ UTR leading to an extended peptide sequence (PMID: 16085695, 21309044). Callewaert with colleagues showed C-terminal frameshift variants in *ELN* to result in enhanced globule formation, increased TGFβ signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis (PMID: 16085695). Inclusion of mutant elastin and normal elastin results in a copolymer that causes reduced and scattered globule deposition on microfibrils. Hence, the variants act through a dominant negative mechanism as maturation of tropoelastin into insoluble elastin is impaired (PMID: 16085695, 20600892, 21309044). Analysis of tissues from mice expressing the hBACCL transgene (generated with *ELN* variant NM_000501.4:c.1946del) found that the mutant protein is incorporated into elastic fibers of skin and lung with adverse effects, but is not well incorporated in the aorta (PMID: 22573328). Another study involving the overexpression of an *ELN* frameshift variant (NM_000501.4:c.1928_1952del) on the normal murine background produced varying pulmonary phenotypes, similar to those observed in some human patients with ADCL, along with overall significant mortality in the transgenic mice; however, no abnormalities of mutant protein expression were observed in the skin and blood vessel (PMID: 20600892). In summary, there is definitive evidence to support the relationship between *ELN* and autosomal dominant cutis laxa. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The mechanism for disease is heterozygous gain of function, dominant-negative effect from a stable C-terminally extended mutant isoform of the elastin protein (PMID: 16085695). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This classification was approved by the Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease Gene Curation Expert Panel on the meeting date October 4th, 2024 (Gene-Disease Validity SOP, version 11).

familial thoracic aortic aneurysm and aortic dissectionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Ambry Genetics

supravalvular aortic stenosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008504

Submitter: Labcorp Genetics (formerly Invitae)

supravalvular aortic stenosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008504

Submitter: PanelApp Australia

cutis laxa, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007411

Submitter: Labcorp Genetics (formerly Invitae)

cutis laxa, autosomal dominant 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007411

Submitter: G2P

supravalvular aortic stenosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008504

Submitter: Ambry Genetics

cutis laxa, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007411

Submitter: PanelApp Australia

supravalvular aortic stenosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008504

Submitter: Orphanet

autosomal dominant cutis laxaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019571

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cutis laxa, autosomal dominant 1; Supravalvular aortic stenosisAD

Manifestation: Cardiovascular; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Pulmonary

Intervention: Cardiovascular

Rationale: In Cutis laxa, cardiovascular anomalies (eg, aortic aneuryms and pulmonary artery stenosis) are frequent, and surveillance to allow efficient detection and treatment/precautionary measures may be beneficial; In supravalvular aortic stenosis, there is a wide range of severity, including sudden infant death, and early diagnosis and treatment (eg, with surgery in some individuals) may reduce morbidity and mortality

Comments: Individuals with Cutis Laxa may have a clinically recognizable phenotype,

Refs: 5046633; 8475063; 8362925; 8364568; 8091333; 8132745; 8541862; 9215670; 9215671; 9873040; 11175284; 15955094; 16085695; 18348261; 19844261

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ELN variants in ClinVar

30 Conditions Cataloged

Supravalvar aortic stenosisTotal: 1029

not providedTotal: 384

not specifiedTotal: 208

ELN-related disorderTotal: 128

Cutis laxa, autosomal dominant 1Total: 100

Inborn genetic diseasesTotal: 99

Williams syndromeTotal: 25

Familial thoracic aortic aneurysm and aortic dissectionTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000501.4. 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			14 clinvar	204 clinvar	2 clinvar	220
missense	3 clinvar	4 clinvar	365 clinvar	62 clinvar	2 clinvar	436
nonsense	25 clinvar	6 clinvar				31
start loss	2 clinvar	3 clinvar				5
frameshift	85 clinvar	36 clinvar	2 clinvar			123
splice donor/acceptor (+/-2bp)	14 clinvar	48 clinvar	23 clinvar			85
Total	129	97	404	266	4	900

Highest pathogenic variant AF is 0.00011524207

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 381 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000501.4	RefSeq	NP_000492.2	33	MANE Select
ENST00000252034.12	Ensembl	ENSP00000252034.7	33	MANE Select
NM_001081752.3	RefSeq	NP_001075221.1	30	Standard
NM_001081753.3	RefSeq	NP_001075222.1	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Lung fibrosis
Integrin

Biological Process

outflow tract morphogenesis
aortic valve morphogenesis
respiratory gaseous exchange
blood circulation
cell population proliferation

Molecular Function

extracellular matrix structural constituent
protein binding
extracellular matrix constituent conferring elasticity

Cellular Component

extracellular region
extracellular matrix
collagen-containing extracellular matrix
elastic fiber

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252034
Coding exons: 33
Length: 42119
Individuals with no LoFs: 125665
Homozygous LoFs: 0
Heterozygous LoFs: 83
Defined: 125748
p: 0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0484	427	430	0.993	0.0000269	4287
Missense (PolyPhen)
Synonymous	-0.947	194	178	1.09	0.0000138	1813
Loss of Function	2.26	29	45.4	0.639	0.00000223	538

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00065	0.00065	rare
Finnish	0.00088	0.00088	rare
European (Non-Finnish)	0.00026	0.00026	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. Molecular determinant of the late arterial morphogenesis, stabilizing arterial structure by regulating proliferation and organization of vascular smooth muscle (By similarity). {ECO:0000250|UniProtKB:P54320}.;
Disease: DISEASE: Cutis laxa, autosomal dominant, 1 (ADCL1) [MIM:123700]: 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. Additional variable clinical features are gastrointestinal diverticula, hernia, and genital prolapse. Rare manifestations are pulmonary artery stenosis, aortic aneurysm, bronchiectasis, and emphysema. {ECO:0000269|PubMed:9873040}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Supravalvular aortic stenosis (SVAS) [MIM:185500]: Congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams-Beuren syndrome. {ECO:0000269|PubMed:10942104}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=ELN is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of ELN may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease (PubMed:8812460). {ECO:0000269|PubMed:8812460}.;

Intolerance Scores

LoFtool: 0.815
RVIS EVS: -0.08
RVIS percentile EVS: 47.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.750

Gene Damage Prediction

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