rs193922239 — FBN1

Pathogenic missense variant in fibrillin-1 replacing glycine 2627 with arginine in a calcium-binding EGF-like domain, disrupting microfibril assembly and predisposing heterozygous carriers to Marfan syndrome with aortic root dilation, lens dislocation, and skeletal overgrowth.

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FBN1 Gly2627Arg — A Crack in the Connective Tissue Scaffold

Every arterial wall, every lens zonule, every ligament that holds your skeleton together depends on a microscopic scaffolding called the microfibril11 microfibril
a rope-like structure in the extracellular matrix assembled from fibrillin-1 molecules end-to-end, providing elasticity and tensile strength to connective tissue throughout the body. Fibrillin-1 is encoded by FBN1 — a 66-exon gene on chromosome 15 producing a 2,871-amino-acid glycoprotein studded with 47 epidermal growth factor-like (EGF-like) domains. Forty-three of these domains are calcium-binding (cbEGF), and calcium ions are essential to their structural rigidity. A single amino acid substitution in any one of these domains can be enough to compromise the entire fibrillin polymer.

The p.Gly2627Arg substitution — coded by two different nucleotide changes at the same genomic position (NC_000015.10:g.48415708C>G or C>T, both producing the same coding-strand change c.7879G>C or c.7879G>A on the minus-strand FBN1 transcript) — replaces a small, flexible glycine with a bulky, positively charged arginine at position 2627 of fibrillin-1. This position sits within a cbEGF-like domain in the C-terminal half of the protein. ClinVar classifies this variant as Pathogenic/Likely Pathogenic with multiple independent submissions22 Pathogenic/Likely Pathogenic with multiple independent submissions
ClinVar VCV000372606, criteria provided, multiple submitters, no conflicts, including a 2025 Pathogenic classification from Labcorp Genetics/Invitae. The variant is essentially absent from population databases (not detected in ALFA across

187,000 alleles), consistent with its role as a rare, high-penetrance disease allele.

The Mechanism

Glycine residues in EGF-like domains serve as structural pivots33 Glycine residues in EGF-like domains serve as structural pivots
glycine's side chain is a single hydrogen atom, making it uniquely suited for tight turns and compact folds that other amino acids cannot achieve. Substituting glycine with arginine introduces a large, charged side chain that distorts the calcium-binding loop. When calcium fails to bind correctly, the cbEGF domain cannot fold into its normal rigid rod-like conformation. This locally misfolded domain then disrupts the folding of adjacent domains through a propagation effect, ultimately destabilizing the entire fibrillin-1 monomer. Abnormal fibrillin-1 impairs microfibril polymerization through a dominant-negative mechanism44 dominant-negative mechanism
the defective monomer interferes with the assembly of normal monomers into functional microfibrils, so even one mutant copy disrupts the whole network, explaining why a single heterozygous copy is sufficient to cause disease.

Beyond structural weakness, impaired fibrillin-1 microfibrils fail to sequester transforming growth factor-beta (TGF-β) in the extracellular matrix. Excessive free TGF-β signaling drives aortic smooth muscle cell dysfunction, progressive aortic wall stiffening, and the aneurysmal dilatation that is the leading cause of premature death in Marfan syndrome.

The Evidence

Dietz et al. (Genomics, 1993)55 Dietz et al. (Genomics, 1993) established that all known FBN1 missense mutations causing classic Marfan syndrome at that time fell at residues with calcium-binding significance in EGF-like domains — the same structural domain affected by Gly2627Arg. The clinical phenotype associated with cbEGF missense mutations is consistently severe, including cardiovascular, ocular, and skeletal manifestations.

The most important clinical outcome data come from the French Marfan cohort followed by Milleron et al. (JACC, 2020)66 Milleron et al. (JACC, 2020): 954 patients with FBN1 pathogenic variants followed over 8,594 patient-years showed that type A aortic dissection occurred at only 0.4 events per 1,000 patient-years when the maximal aortic diameter remained below 50 mm with guideline-directed treatment (beta-blockers, exercise restriction). The key message: risk is manageable when diagnosed early and monitored diligently.

On the treatment side, Brooke et al. (N Engl J Med, 2008)77 Brooke et al. (N Engl J Med, 2008) demonstrated that the angiotensin receptor blocker losartan reduced aortic root dilation rate from 3.54 mm/yr to 0.46 mm/yr in 18 pediatric Marfan patients — an approximately 87% reduction — by blocking TGF-β pathway activation. This finding underpins the current guideline recommendation to add an ARB if aortic progression rate exceeds 5 mm/year or root diameter exceeds 40 mm in children.

Practical Actions

FBN1 pathogenic variant carriers require structured, lifelong cardiac surveillance. Annual transthoracic echocardiography is the standard; cardiac MRI can be added for improved accuracy, especially at the aortic sinuses and ascending aorta. Medical therapy with a beta-blocker or ARB (commonly losartan) reduces hemodynamic stress on the aortic wall and should be initiated at diagnosis or upon confirming progressive dilation. Prophylactic aortic root surgery is recommended when the root approaches 5.0 cm in adults or progresses rapidly regardless of absolute diameter.

Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin) are contraindicated for this genotype — they inhibit lysyl oxidase, the enzyme responsible for cross-linking collagen and elastin, and have been linked to aortic aneurysm rupture and dissection in connective tissue disorder patients. Decongestants and vasoconstrictors (including nasal decongestants, triptans for migraine) should be used only under medical supervision given their effects on aortic wall stress.

Annual ophthalmologic examination is also indicated: approximately 60% of Marfan patients develop ectopia lentis (lens dislocation) and are at elevated risk for retinal detachment and glaucoma.

Interactions

The dominant-negative mechanism of FBN1 missense mutations means that second-hit variants in fibrillin-1 or in related extracellular matrix genes are unlikely (two pathogenic FBN1 alleles causes a severe neonatal Marfan phenotype that is not typically compatible with adulthood). However, modifier effects in TGF-β pathway genes (TGFBR1, TGFBR2, SMAD2, SMAD3) have been described in related connective tissue disorders — Loeys-Dietz syndrome — and may influence phenotypic severity in FBN1 carriers. Carriers who also have variants in ACTA2 or MYH11 (smooth muscle genes associated with familial thoracic aortic aneurysm) may warrant more aggressive surveillance thresholds, though formal compound genotype data for this specific FBN1 variant are not published.

Drug Interactions

fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

No FBN1 Gly2627Arg variant detected

You carry two copies of the reference C allele at this position. The p.Gly2627Arg pathogenic fibrillin-1 variant is not present in your genome at this locus. This variant is not detected in large population databases (>187,000 alleles screened) and is present only in individuals with Marfan syndrome or related connective tissue disorders. The common result at this position — by an overwhelming margin — is two reference copies.

CG Pathogenic Carrier High Risk

Carries one copy of the FBN1 p.Gly2627Arg pathogenic variant — Marfan syndrome risk

The glycine-to-arginine substitution at position 2627 of fibrillin-1 introduces a bulky positively charged side chain into a calcium-binding EGF-like (cbEGF) domain in the C-terminal region of the protein. Calcium coordination by cbEGF domains is essential for the rigid rod conformation that fibrillin-1 monomers require to polymerize into functional microfibrils. Disruption of this fold produces a dominant-negative effect: the malformed monomer interferes with assembly of normal monomers, impairing the integrity of the entire microfibril network even though the other FBN1 allele remains intact.

Weakened microfibrils compromise the structural integrity of the aortic wall, the lens zonules, and the skeletal connective tissue. In the aorta, reduced microfibril support is compounded by impaired TGF-β sequestration: excess free TGF-β drives smooth muscle cell dysregulation, progressive stiffening, and aneurysmal dilation at the sinuses of Valsalva — the aortic root. Once aortic diameter reaches 50 mm in adults, the risk of catastrophic dissection rises steeply, justifying prophylactic surgical repair.

In the largest cohort study (954 FBN1 pathogenic variant carriers, 8,594 patient-years), the rate of type A aortic dissection was only 0.4 events per 1,000 patient-years when diameter was kept below 50 mm with beta-blocker therapy and exercise restriction. This low rate is achievable with regular specialist follow-up — it is not the natural history without treatment.

Note that a separate substitution at the same nucleotide position (c.7879G>A, plus-strand C>T, ClinVar VCV000036122) also causes p.Gly2627Arg and is classified Pathogenic/Likely Pathogenic by multiple laboratories. Both nucleotide substitutions at this site carry the same clinical implications; the CT genotype at this locus should be interpreted identically to CG.

Any consumer or research-grade genotyping result for this variant should be confirmed by a CLIA-certified clinical laboratory before medical decisions are made. Clinical-grade FBN1 sequencing panels also detect the full spectrum of pathogenic variants across all 66 exons, which is important for family cascade planning.

GG Homozygous (Extremely Rare) High Risk

Appears to carry two copies of the FBN1 Gly2627Arg pathogenic variant — an exceptionally rare finding

Homozygous pathogenic FBN1 mutations are documented only in neonatal Marfan syndrome — one of the most severe congenital connective tissue presentations, with aortic root dilation apparent in utero or within the first days of life, mitral and tricuspid valve insufficiency, severe respiratory distress from pulmonary involvement, and extreme skeletal features. Survival beyond infancy without aggressive surgical intervention is exceptional.

Given the extreme rarity of this genotype and the probability that it would produce severe neonatal disease, an individual presenting in adulthood with an apparent GG result at this locus almost certainly represents either a technical artifact or a de novo appearance that merits independent confirmation. Do not act on this result without laboratory confirmation.