FBN1

Chr 15AD

fibrillin 1

Also known as: ACMICD, ECTOL1, FBN, GPHYSD2, MASS, MFLS, MFS1, OCTD

NCBI Gene: 2200 ENSG00000166147 OMIM: 134797

The protein fibrillin-1 forms calcium-binding microfibrils that provide structural support in elastic and nonelastic connective tissue throughout the body, while the co-encoded hormone asprosin regulates glucose homeostasis. Mutations cause autosomal dominant connective tissue disorders including Marfan syndrome, MASS syndrome, ectopia lentis, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome, and several other related conditions. The pathogenic mechanism involves loss of function, leading to compromised structural integrity of connective tissues.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.058 OMIM phenotypes

Clinical Summary— FBN1

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Gene-Disease Validity (ClinGen)

Marfan syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.05LOEUF

pLI 1.000

Z-score 11.46

OE 0.02 (0.01–0.05)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.06Z-score

OE missense 0.64 (0.61–0.68)

1038 obs / 1609.8 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.05)

0≤0.351.4

Missense OE?0.64 (0.61–0.68)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 3 / 158.8Missense obs/exp: 1038 / 1609.8Syn Z: 0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedFBN1-related isolated ectopia lentisOTHERAD

strongFBN1-related Weill-Marchesani syndromeOTHERAD

definitiveFBN1-related Marfan syndrome (biallelic)LOFAR

definitiveFBN1-related Marfan syndrome (monoallelic)LOFAD

This gene — mechanism propensity

0.2997th %ile

GOF

0.3788th %ile

LOF

0.74top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.05 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNMFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene.1

LOFA pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%).2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

FBN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Cardiomyopathy, HypertrophicCardiomyopathy, DilatedCardiomyopathy Restrictive

National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil's Unified Health System Through a Multicenter Registry

RECRUITING

NCT06546137Hospital do CoracaoStarted 2025-04-30

whole genome sequencing

Marfan SyndromeMarfan's Syndrome With Cardiovascular Manifestations

Transcriptomic Study of Adult Population With Marfan Syndrome

ACTIVE NOT RECRUITING

NCT05700175IRCCS Policlinico S. DonatoStarted 2021-11-02

Transcriptomic, epigenetic and proteomic analysis

Lipodystrophy (Genetic or Acquired, Non HIV)

The LD Lync Study - Natural History Study of Lipodystrophy Syndromes

RECRUITING

NCT03087253University of MichiganStarted 2018-02-27