rs140597 — FBN1 D1113G

Pathogenic missense variant in fibrillin-1 replacing the calcium-coordinating aspartate at position 1113 with glycine in an EGF-like calcium-binding domain, disrupting microfibril assembly and predisposing heterozygous carriers to familial thoracic aortic aneurysm and dissection (FTAAD) and Marfan syndrome

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FBN1 Asp1113Gly — A Missing Anchor in the Aortic Wall

The aorta tolerates tens of millions of pressure pulses over a lifetime because its wall is reinforced by an elastic scaffold made of microfibrils11 microfibrils
rope-like extracellular matrix structures assembled from fibrillin-1 molecules linked end-to-end, providing elasticity and tensile strength throughout connective tissue. Fibrillin-1 is a 2,871-amino-acid glycoprotein encoded by FBN1 on chromosome 15. It contains 47 epidermal growth factor-like (EGF-like) domains, 43 of which are calcium-binding (cbEGF). Each cbEGF domain requires calcium to fold into a rigid rod — calcium ions are not just incidental cofactors but the structural glue that holds the entire module together. Aspartate residues at conserved positions within these domains directly coordinate the calcium ion, and substituting any one of them disrupts the fold.

The p.Asp1113Gly variant (coding-strand c.3338A>G on the minus-strand FBN1 transcript; plus-strand T→C at chr15:48,487,437) removes the calcium-coordinating aspartate at position 1113 and replaces it with glycine — the smallest amino acid, with no side chain at all. ClinVar classifies this variant as Pathogenic or Likely Pathogenic across three independent submissions (RCV000663632, RCV000802396, RCV002284420), with conditions listed as Marfan syndrome and familial thoracic aortic aneurysm and aortic dissection (FTAAD). The global allele frequency of the C allele is approximately 0.02% (20 of 88,940 ALFA samples), consistent with a rare, high-penetrance disease variant under negative selection.

The Mechanism

Within a cbEGF domain, a conserved sequence motif coordinates a single calcium ion through the side chains of several residues — aspartate residues contribute critically to this coordination shell. Disrupting calcium coordination destabilizes the cbEGF fold22 Disrupting calcium coordination destabilizes the cbEGF fold
Dietz et al. 1993 showed that all early Marfan syndrome missense mutations at that time affected residues with calcium-binding significance in EGF-like domains, preventing fibrillin-1 from achieving the extended rigid conformation needed for microfibril polymerization. The misfolded monomer acts through a dominant-negative mechanism33 dominant-negative mechanism
the defective protein physically interferes with normal fibrillin-1 assembly, impairing the entire microfibril network even when the second FBN1 allele is intact — which is why a single copy of this variant is sufficient to cause disease.

Weakened microfibrils in the aortic media reduce mechanical resilience of the aortic wall and, importantly, fail to sequester transforming growth factor-beta (TGF-β) in the extracellular matrix. Excess free TGF-β drives smooth muscle cell dysfunction, progressive aortic wall stiffening, and aneurysmal dilation at the sinuses of Valsalva — the anatomical pinch-point where nearly all Marfan-related dissections originate.

The Evidence

The broader clinical evidence base for FBN1 cbEGF domain missense variants predicting aortic disease is well-established:

Tan et al. (Human Molecular Genetics, 2017)44 Tan et al. (Human Molecular Genetics, 2017) sequenced FBN1 in 687 patients with sporadic non-syndromic aortic dissection and found pathogenic FBN1 variants in 3.9% (27 patients), the majority being missense mutations — demonstrating that FBN1 pathogenic variants cause FTAAD even in the absence of full syndromic Marfan features.

The most important prognostic data for FBN1 pathogenic variant carriers come from Milleron et al. (JACC, 2020)55 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 maximum aortic diameter remained below 50 mm on guideline-directed treatment. This is a critically important number: risk is not inevitable but is profoundly modifiable by structured surveillance and timely intervention.

On treatment, Brooke et al. (NEJM, 2008)66 Brooke et al. (NEJM, 2008) showed that losartan (an angiotensin receptor blocker that blocks TGF-β pathway overactivation) reduced aortic root dilation rate from 3.54 mm/yr to 0.46 mm/yr in 18 pediatric Marfan patients — approximately an 87% reduction. This finding underpins current guidelines recommending ARBs when aortic root dilation progresses faster than 5 mm/year or root diameter exceeds 40 mm in children.

Practical Actions

The cornerstone of management is annual transthoracic echocardiography to track aortic root diameter at the sinuses of Valsalva. Medical therapy with a beta-blocker (to reduce heart rate and aortic wall stress) or ARB (losartan, to block excess TGF-β signaling) should be initiated at diagnosis or upon detecting progressive dilation. Prophylactic aortic root replacement is recommended when the aortic root approaches 5.0 cm in adults (4.5–5.0 cm in rapid progressors or patients with a family history of dissection).

Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin) inhibit lysyl oxidase — the enzyme that cross-links collagen and elastin — and carry an FDA black-box warning for aortic aneurysm rupture and dissection risk, particularly in patients with connective tissue disorders. All prescribers must be informed of this contraindication.

Strenuous isometric exercise (heavy weightlifting, contact sports, competitive athletics) should be avoided — these modalities generate abrupt spikes in arterial pressure that place disproportionate mechanical stress on an already vulnerable aortic wall.

Cascade genetic testing of first-degree relatives is clinically essential. A single positive finding in one family member should trigger testing of all parents, siblings, and adult children, since autosomal dominant transmission gives each relative a 50% chance of carrying the variant — and several may harbor silent aortic dilation detectable only by imaging.

Interactions

FBN1 pathogenic variants, including D1113G, interact clinically with variants in TGF-β pathway genes (TGFBR1, TGFBR2, SMAD2, SMAD3) — the genetic basis of Loeys-Dietz syndrome. Carriers who also harbor pathogenic variants in ACTA2 (smooth muscle alpha-actin) or MYH11 (smooth muscle myosin heavy chain), both associated with independent familial TAAD syndromes, may warrant more aggressive surveillance thresholds, though formal compound genotype data for D1113G specifically are not published.

Other FBN1 cbEGF domain missense variants in the database — including rs193922239 (p.Gly2627Arg) — share the same dominant-negative mechanism and clinical management protocol. The diagnosis of Marfan syndrome versus FTAAD-without-full-Marfan-features depends on the presence of ocular and skeletal manifestations alongside the cardiovascular findings; either presentation requires the same aortic surveillance program.

Drug Interactions

fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-Carrier Normal

No FBN1 D1113G variant — no elevated aortic risk from this locus

You carry two copies of the reference T allele at this position. The p.Asp1113Gly pathogenic fibrillin-1 variant is not present in your genome at this locus. This variant is absent from large population databases at detectable frequency and is found essentially only in individuals with Marfan syndrome or familial thoracic aortic disease. The overwhelmingly common result — by a margin of approximately 4,999 in 5,000 — is two reference copies.

CT Pathogenic Carrier High Risk

Carries one copy of FBN1 D1113G — pathogenic variant for FTAAD and Marfan syndrome

The Asp1113Gly substitution removes a negatively charged aspartate side chain at a conserved calcium-coordination position within a cbEGF domain in the N-terminal half of fibrillin-1. Calcium coordination by cbEGF domains is essential for the rigid rod conformation that fibrillin-1 monomers require to polymerize into functional microfibrils. Disruption of the cbEGF fold produces a dominant-negative effect: the misfolded monomer interferes with the assembly of normal monomers, impairing the entire extracellular matrix microfibril network even though the second FBN1 allele remains intact.

The clinical consequence unfolds primarily at the aortic root: weakened microfibrils reduce mechanical resilience of the aortic media, and impaired TGF-β sequestration drives progressive smooth muscle cell dysfunction and aneurysmal dilation at the sinuses of Valsalva. ClinVar submissions link this variant to both full Marfan syndrome (with potential ocular and skeletal involvement) and FTAAD (cardiovascular-predominant presentations), reflecting the phenotypic spectrum of FBN1 cbEGF domain missense mutations.

In the largest FBN1 cohort study (954 patients, 8,594 patient-years), the annual type A aortic dissection rate was only 0.4 events per 1,000 patient-years when maximum aortic diameter was kept below 50 mm with beta-blocker therapy and activity restriction. This demonstrates that risk is manageable with specialist follow-up — it is not an inevitable outcome.

This variant is absent from large population databases at detectable frequency (not observed in >115,000 European alleles in ALFA), consistent with a rare, high-penetrance disease allele under negative selection. Any genotyping result for this variant should be confirmed by a CLIA-certified clinical laboratory before medical decisions are taken.

CC Homozygous Homozygous

Carries two copies of FBN1 D1113G — extremely rare, severe FTAAD/Marfan risk

You carry two copies of the C allele at this position, corresponding to homozygosity for the FBN1 p.Asp1113Gly pathogenic variant. This is an exceptionally rare genotype: the C allele is present in approximately 0.02% of the global population, and homozygosity would require both parents to carry the variant. Biallelic pathogenic FBN1 mutations typically produce severe neonatal Marfan syndrome with rapidly progressive cardiovascular and systemic features, though the phenotype of homozygous D1113G specifically has not been reported in published literature. Management follows the same principles as for heterozygous carriers, with a heightened index of suspicion for severe or early-onset disease, and with the certainty that every biological child will inherit at least one C allele.