FBLN5

fibulin 5, the group of Fibulins

Basic information

Region (hg38): 14:91869410-91947987

Links

ENSG00000140092 ∙ NCBI:10516 ∙ OMIM:604580 ∙ HGNC:3602 ∙ Uniprot:Q9UBX5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cutis laxa, autosomal recessive, type 1A (Strong), mode of inheritance: AR
• cutis laxa, autosomal dominant 2 (Strong), mode of inheritance: AD
• cutis laxa, autosomal recessive, type 1A (Strong), mode of inheritance: AR
• cutis laxa, autosomal recessive, type 1A (Moderate), mode of inheritance: Semidominant
• macular degeneration, age-related, 3 (Moderate), mode of inheritance: AD
• autosomal dominant cutis laxa (Supportive), mode of inheritance: AD
• autosomal recessive cutis laxa type 1 (Supportive), mode of inheritance: AR
• hereditary sensorimotor neuropathy with hyperelastic skin (Supportive), mode of inheritance: AD
• cutis laxa, autosomal dominant 2 (Definitive), mode of inheritance: AD
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H (Strong), mode of inheritance: AD
• demyelinating hereditary motor and sensory neuropathy (Moderate), mode of inheritance: AD
• cutis laxa, autosomal recessive, type 1A (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
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	AD/AR	General	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	Dermatologic; Cardiovascular; Gastrointestinal; Genitourinary; Neurologic; Ophthalmologic; Pulmonary	12189163; 12618961; 15269314; 20301756; 22829427

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FBLN5 gene.

• not provided (383 variants)
• Macular degeneration, age-related, 3 (60 variants)
• Cutis laxa (54 variants)
• not specified (20 variants)
• Inborn genetic diseases (18 variants)
• Age-related macular degeneration (7 variants)
• Cutis laxa, autosomal dominant 2 (6 variants)
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H (4 variants)
• Cutis laxa, autosomal recessive, type 1A (4 variants)
• Cutis laxa, autosomal dominant (3 variants)
• Macular degeneration (3 variants)
• Cutis Laxa, Dominant/Recessive (3 variants)
• FBLN5-related condition (2 variants)
• Hereditary sensorimotor neuropathy with hyperelastic skin (2 variants)
• Tip-toe gait (1 variants)
• Cutis laxa, autosomal recessive, type 1A;Cutis laxa, autosomal dominant 2 (1 variants)
• See cases (1 variants)
• Macular degeneration, age-related, 3;Cutis laxa, autosomal dominant 2;Cutis laxa, autosomal recessive, type 1A (1 variants)
• Cutis laxa, autosomal dominant 2;Macular degeneration, age-related, 3;Cutis laxa, autosomal recessive, type 1A (1 variants)
• Peripheral axonal neuropathy (1 variants)
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H;Cutis laxa, autosomal recessive, type 1A;Cutis laxa, autosomal dominant 2;Macular degeneration, age-related, 3 (1 variants)
• Cutis laxa, autosomal dominant 2;Charcot-Marie-Tooth disease, demyelinating, IIA 1H;Cutis laxa, autosomal recessive, type 1A;Macular degeneration, age-related, 3 (1 variants)
• Retinal dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FBLN5 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	77	2	81
missense			151		1	152
nonsense	1	1	5			7
start loss						0
frameshift	1					1
inframe indel			6			6
splice donor/acceptor (+/-2bp)			2			2
splice region			6	10		16
non coding			16	91	37	144
Total	2	1	182	168	40

Variants in FBLN5

This is a list of pathogenic ClinVar variants found in the FBLN5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-91869449-T-G		Macular degeneration, age-related, 3 • Cutis laxa	Uncertain significance (Jan 13, 2018)
14-91869571-C-T		Cutis laxa • Macular degeneration, age-related, 3	Uncertain significance (Jan 13, 2018)
14-91869576-C-T		Macular degeneration, age-related, 3 • Cutis laxa	Conflicting classifications of pathogenicity (Jan 13, 2018)
14-91869577-G-A		Macular degeneration, age-related, 3 • Cutis laxa	Benign/Likely benign (Jan 12, 2018)
14-91869601-T-A		Macular degeneration, age-related, 3 • Cutis laxa	Benign (May 19, 2021)
14-91869710-T-C		Macular degeneration, age-related, 3 • Cutis laxa	Benign/Likely benign (May 18, 2021)
14-91869766-A-G		Cutis laxa • Macular degeneration, age-related, 3	Uncertain significance (Jan 13, 2018)
14-91869798-G-A		Cutis laxa • Macular degeneration, age-related, 3	Uncertain significance (Jan 13, 2018)
14-91869801-A-G		Cutis laxa • Macular degeneration, age-related, 3	Benign/Likely benign (Jan 12, 2018)
14-91869805-C-G		Cutis laxa • Macular degeneration, age-related, 3	Uncertain significance (Jan 12, 2018)
14-91869861-G-A		Cutis laxa • Macular degeneration, age-related, 3	Uncertain significance (Jan 13, 2018)
14-91869895-A-G		Macular degeneration, age-related, 3 • Cutis laxa	Benign (Jan 13, 2018)
14-91869898-C-T		Cutis laxa • Macular degeneration, age-related, 3	Benign (Jan 13, 2018)
14-91870103-G-A		Macular degeneration, age-related, 3 • Cutis laxa	Uncertain significance (Jan 13, 2018)
14-91870126-C-T		Macular degeneration, age-related, 3 • Cutis laxa	Uncertain significance (Jan 13, 2018)
14-91870147-A-T		Cutis laxa • Macular degeneration, age-related, 3	Uncertain significance (Jan 12, 2018)
14-91870229-A-G			Uncertain significance (Dec 28, 2023)
14-91870230-T-C		not specified	Likely benign (Jan 06, 2024)
14-91870236-C-G		Inborn genetic diseases	Uncertain significance (Apr 18, 2023)
14-91870237-T-A		Retinal dystrophy	Uncertain significance (May 21, 2017)
14-91870237-T-G		Inborn genetic diseases	Uncertain significance (Jan 09, 2024)
14-91870239-C-A			Likely benign (Apr 25, 2023)
14-91870239-C-T			Likely benign (Oct 13, 2023)
14-91870240-G-A			Uncertain significance (Jan 08, 2024)
14-91870244-C-T			Uncertain significance (Dec 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FBLN5	protein_coding	protein_coding	ENST00000342058	11	78576

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000301	125741	0	2	125743	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.56	199	271	0.734	0.0000175	2947
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00000898	0.00000879
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Extracellular matrix organization;Molecules associated with elastic fibres;Elastic fibre formation (Consensus)

Recessive Scores

• pRec: 0.175

Intolerance Scores

• loftool: 0.0398
• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.59

Haploinsufficiency Scores

• pHI: 0.338
• hipred: Y
• hipred_score: 0.685
• ghis: 0.591

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.545

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fbln5
• Phenotype: neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); respiratory system phenotype; muscle phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype

Gene ontology

• Biological process: regulation of cell growth;cell-matrix adhesion;extracellular matrix organization;protein localization to cell surface;secretion;elastic fiber assembly;regulation of removal of superoxide radicals
• Cellular component: extracellular region;extracellular space;extracellular matrix;collagen-containing extracellular matrix;extracellular exosome;elastic fiber
• Molecular function: integrin binding;calcium ion binding;protein binding;protein C-terminus binding;extracellular matrix constituent conferring elasticity;protein homodimerization activity