FBLN5

protein-coding

fibulin 5, the group of Fibulins

Gene summary

The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

MANE transcript

NM_006329.4

Inheritance

AD, AR, SD

ClinVar variants

P:15U:302B:140

Top phenotype

Neuropathy, hereditary, with or witout age-related macular degeneration; Macular degeneration, age-related, 3; Cutis laxa, autosomal dominant 2; Cutis laxa, autosomal recessive, type IA

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr14:91,869,411-91,947,987

External References & Databases

Ensembl (ENSG00000140092)

Transcript & Mutation Effects

hg38 • Region Span ~78.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cutis laxa, autosomal dominant 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013751

Submitter: G2P

autosomal recessive cutis laxa type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019572

Submitter: Orphanet

autosomal dominant cutis laxaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019571

Submitter: Orphanet

cutis laxa, autosomal recessive, type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009052

Submitter: PanelApp Australia

demyelinating hereditary motor and sensory neuropathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018776

Submitter: PanelApp Australia

cutis laxa, autosomal dominant 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013751

Submitter: PanelApp Australia

cutis laxa, autosomal recessive, type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009052

Submitter: Labcorp Genetics (formerly Invitae)

hereditary sensorimotor neuropathy with hyperelastic skinSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017237

Submitter: Orphanet

demyelinating hereditary motor and sensory neuropathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018776

Submitter: ClinGen

FBLN5 was first reported in relation to autosomal dominant demyelinating hereditary motor and sensory neuropathy in 2011 (PMID: 21576112). FBLN5 is a member of the fibulin family of proteins which are extracellular matrix proteins characterized by tandem arrays of EGF-like domains and a C-terminal fibulin-type module. This gene consists of 11 exons that are differentially combined in three major transcripts. FBLN5 is also reported in association with autosomal dominant and recessive cutis laxa, a connective tissue disorder, and autosomal dominant age-related macular degeneration. Available data and input from our expert panel indicates these phenotypes should be split: there is phenotypic variability, differences in inheritance pattern (autosomal recessive, autosomal dominant, and autosomal dominant with age-related penetrance), and differences in molecular mechanism (cutis laxa variants are biallelic loss of function or heterozygous dominant-negative, which is different from the variants associated with macular degeneration and neuropathy). However, there are cases with overlapping features suggesting a possible phenotypic spectrum. For example, many of the individuals referenced in this curation have neuropathy with variable connective tissue features (hyperelastic skin, hypermobility) and age-related macular degeneration. There is at least one variant that has been reported in both individuals with neuropathy and in individuals with isolated age-related macular dystrophy (p.G267S, PMID: 21576112). In this curation, we scored evidence for 6 missense variants in over 15 families (some with shared haplotype)- p.G90S, p.V126M, p.G267S, p.D329V, p.R331H, and p.R373C (PMIDs: 21576112, 23328402, 28332470, 31945625, 32757322). A single variant (p.R373C) arose in multiple unique haplotypes and is considered a hotspot variant. Age of onset and phenotype varied between and within families but generally consisted of adult-onset progressive peripheral sensorimotor neuropathy with foot deformities, upper and lower limb sensory disturbances, and impaired gait with or without hypo/areflexia, muscle weakness, hyperelastic skin, hypermobility, and age-related macular degeneration. The mechanism of pathogenicity appears to be loss-of-function. Genetic evidence score totaled 3.1. Of note, there are additional families and variants not included in this curation as insufficient clinical data was reported (e.g. lack of electromyography to confirm neuropathy). A single publication reports extensive experimental evidence including expression data, non-patient cell functional alteration, non-human model organism, and rescue in a non-human model organism (PMID: 33107705). The non-human (zebrafish) model showed that lack of FBLN5 leads to myelination defects which can be rescued to normal myelination levels with exogenous overexpression of FBLN5. Experimental evidence score is 5. The total score is 8.1. In summary, FBLN5 is moderately associated with autosomal dominant demyelinating hereditary motor and sensory neuropathy. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.

cutis laxa, autosomal recessive, type 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009052

Submitter: G2P

macular degeneration, age-related, 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012145

Submitter: Ambry Genetics

cutis laxa, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013751

Submitter: Genomics England PanelApp

cutis laxa, autosomal recessive, type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009052

Submitter: Genomics England PanelApp

cutis laxa, autosomal recessive, type 1AMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0009052

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease, demyelinating, IIA 1HSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030689

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neuropathy, hereditary, with or witout age-related macular degeneration; Macular degeneration, age-related, 3; Cutis laxa, autosomal dominant 2; Cutis laxa, autosomal recessive, type IAAD/AR

Manifestation: Dermatologic; Cardiovascular; Gastrointestinal; Genitourinary; Neurologic; Ophthalmologic; Pulmonary

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12189163; 12618961; 15269314; 20301756; 22829427

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBLN5 variants in ClinVar

21 Conditions Cataloged

not providedTotal: 578

not specifiedTotal: 57

Inborn genetic diseasesTotal: 54

Macular degeneration, age-related, 3Total: 39

FBLN5-related disorderTotal: 31

Cutis laxaTotal: 25

Cutis laxa, autosomal recessive, type 1ATotal: 18

Cutis laxa, autosomal dominant 2Total: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006329.4. 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			5 clinvar	130 clinvar	1 clinvar	136
missense	1 clinvar	8 clinvar	283 clinvar	8 clinvar	1 clinvar	301
nonsense	2 clinvar	3 clinvar	8 clinvar			13
start loss			1 clinvar			1
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	4	11	302	138	2	457

Highest pathogenic variant AF is 0.000054527383

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006329.4	RefSeq	NP_006320.2	11	MANE Select
ENST00000342058.9	Ensembl	ENSP00000345008.4	11	MANE Select
NM_001384158.1	RefSeq	NP_001371087.1	12	Standard
NM_001384159.1	RefSeq	NP_001371088.1	11	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 cell growth
cell-matrix adhesion
extracellular matrix organization
protein localization to cell surface
secretion

Molecular Function

integrin binding
calcium ion binding
protein binding
protein C-terminus binding
extracellular matrix constituent conferring elasticity

Cellular Component

extracellular region
extracellular space
extracellular matrix
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342058
Coding exons: 11
Length: 78576
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125743
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.56	199	271	0.734	0.0000175	2947
Missense (PolyPhen)		39	90.043	0.43313		1090
Synonymous	0.419	100	105	0.948	0.00000747	843
Loss of Function	4.70	1	27.6	0.0362	0.00000153	302

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)	0.0000090	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN (PubMed:18185537). Stabilizes and organizes elastic fibers in the skin, lung and vasculature (By similarity). Promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. Vascular ligand for integrin receptors which may play a role in vascular development and remodeling (PubMed:10428823). May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108). {ECO:0000250|UniProtKB:Q9WVH9, ECO:0000269|PubMed:10428823, ECO:0000269|PubMed:17255108, ECO:0000269|PubMed:18185537}.;
Disease: DISEASE: Neuropathy, hereditary, with or without age-related macular degeneration (HNARMD) [MIM:608895]: An autosomal dominant neuropathy of the Charcot-Marie-Tooth disease group, characterized by distal muscle weakness and atrophy variably affecting the lower and upper limbs. Distal sensory impairment and decreased nerve conduction velocities are present in most but not all patients. Additional variable features are age-related macular degeneration, joint hypermobility, and hyperelastic skin. {ECO:0000269|PubMed:21576112, ECO:0000269|PubMed:23328402}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cutis laxa, autosomal dominant, 2 (ADCL2) [MIM:614434]: 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:12618961}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cutis laxa, autosomal recessive, 1A (ARCL1A) [MIM:219100]: 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. Type I autosomal recessive cutis laxa is a specific, life-threatening disorder with organ involvement, lung atelectasis and emphysema, diverticula of the gastrointestinal and genitourinary systems, and vascular anomalies. Associated cranial anomalies, late closure of the fontanel, joint laxity, hip dislocation, and inguinal hernia have been observed but are uncommon. {ECO:0000269|PubMed:12189163, ECO:0000269|PubMed:16652333, ECO:0000269|PubMed:16691202, ECO:0000269|PubMed:17035250, ECO:0000269|PubMed:18185537, ECO:0000269|PubMed:20007835, ECO:0000269|PubMed:20599547}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations affecting this gene can modify the phenotype of diseases caused by ELN mutations. {ECO:0000269|PubMed:19194475}.; DISEASE: Macular degeneration, age-related, 3 (ARMD3) [MIM:608895]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:15269314, ECO:0000269|PubMed:16652333, ECO:0000269|PubMed:20007835, ECO:0000269|PubMed:20599547}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.175

Intolerance Scores

LoFtool: 0.0398
RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.545

Gene Damage Prediction

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