On this page
FLNC
filamin C
FLNC encodes filamin C, a structural protein critical for maintaining the integrity of cardiac and skeletal muscle cells. The FLNC gene provides instructions for making filamin C, a large protein that helps organise and stabilise the internal scaffold of muscle fibres.
FLNC is located on the long (q) arm of chromosome 7, at band 7q32.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 7 in the library →Overview
The FLNC gene, located on chromosome 7, encodes filamin C, a sarcomeric protein predominantly expressed in cardiac and skeletal muscle tissue. Filamin C belongs to a family of actin-binding proteins that serve as molecular scaffolds, linking the contractile machinery of muscle cells to the plasma membrane and organising intracellular signalling networks. The protein plays an essential role in muscle development, force transmission, and the structural maintenance of muscle fibres during contraction.
Pathogenic changes in FLNC disrupt the normal architecture and function of muscle tissue, leading to a range of inherited myopathies and cardiomyopathies. These conditions vary widely in their clinical presentation, from progressive muscle weakness to life-threatening cardiac arrhythmias and heart failure. FLNC-related disorders follow an autosomal dominant inheritance pattern, meaning a single altered copy of the gene can cause disease. Due to its association with actionable cardiac conditions, FLNC is included in the American College of Medical Genetics and Genomics Secondary Findings list, reflecting the clinical importance of identifying pathogenic variants even when testing is performed for unrelated reasons.
Understanding FLNC and its role in muscle biology is important for both diagnostic evaluation and family planning. Individuals found to carry pathogenic FLNC variants may benefit from cardiac surveillance and personalised management strategies to reduce the risk of serious complications.
What the gene does
Filamin C functions as a structural and signalling scaffold within the sarcomere, the fundamental contractile unit of muscle cells. The protein crosslinks actin filaments into three-dimensional networks, providing mechanical stability to muscle fibres during the repetitive cycles of contraction and relaxation. By anchoring the sarcomeric Z-disc to the plasma membrane, filamin C helps transmit mechanical forces generated during muscle contraction and maintains the spatial organisation of myofibrils.
Beyond its structural role, filamin C coordinates multiple signalling pathways involved in muscle development, repair, and adaptation to mechanical stress. The protein interacts with a diverse array of binding partners, including transmembrane receptors, signalling molecules, and components of the cytoskeleton. These interactions enable filamin C to integrate mechanical and biochemical signals, regulating processes such as myofibril assembly, protein turnover, and stress responses. Research suggests that filamin C modulates the activity of mechanosensitive ion channels and contributes to calcium handling within muscle cells, both of which are critical for normal excitation-contraction coupling.
The protein is particularly abundant in tissues subjected to high mechanical loads. In cardiac muscle, filamin C localises to the Z-disc and intercalated discs, regions where individual cardiomyocytes connect and coordinate their contractile activity. In skeletal muscle, the protein is similarly concentrated at Z-discs and plays a role in maintaining muscle fibre integrity during forceful contractions. Evidence suggests that filamin C also participates in muscle repair and regeneration following injury, helping to restore normal tissue architecture.
Filamin C expression is developmentally regulated, with increased abundance during myogenesis and muscle maturation. The protein's ability to bind multiple partners simultaneously allows it to function as a dynamic hub, adapting its interactions in response to changing cellular conditions. Disruption of these finely tuned interactions through pathogenic variants can compromise both the mechanical properties of muscle tissue and the signalling networks required for proper muscle function.
The actin-binding domain at the protein's N-terminus is essential for filament crosslinking, while the C-terminal region mediates protein-protein interactions and dimerisation. This modular architecture enables filamin C to simultaneously anchor to the actin cytoskeleton and recruit signalling molecules to specific subcellular locations, coordinating structural and regulatory functions within the same protein complex.
Video: Genetics 101
Chromosome location
The FLNC gene is located on the long arm of chromosome 7 at position 32.1, designated as 7q32.1. This chromosomal region contains several genes involved in muscle development and function, reflecting a clustering of functionally related loci. The gene spans a substantial genomic interval and contains multiple exons that encode the 2,725 amino acid filamin C protein.
The precise organisation of regulatory elements upstream and downstream of the FLNC coding sequence helps control tissue-specific expression, ensuring high levels of filamin C production in cardiac and skeletal muscle while limiting expression in other tissues. Genomic variants affecting these regulatory regions can potentially alter expression levels, although most clinically significant FLNC variants occur within the protein-coding sequence itself.
Protein structure
Filamin C is a large, 2,725 amino acid protein with a highly modular architecture that reflects its diverse functional roles. The N-terminal region contains an actin-binding domain spanning amino acids 1-259, which mediates the protein's attachment to actin filaments and enables the formation of crosslinked networks. Within this region, a short disordered segment (amino acids 1-28) precedes two calponin-homology domains: CH1 (amino acids 36-142) and CH2 (amino acids 159-262). These tandem CH domains fold together to create the functional actin-binding site, with precise spacing and orientation critical for effective filament recognition and crosslinking.
The central and C-terminal portions of filamin C consist of an extended series of immunoglobulin-like filamin repeats. The protein contains multiple repeats spanning the middle and C-terminal regions of the molecule. The listed repeats-Filamin 1 (amino acids 270-368), Filamin 2 (amino acids 370-468), Filamin 3 (amino acids 469-565), Filamin 4 (amino acids 566-658), Filamin 5 (amino acids 662-758), Filamin 6 (amino acids 759-861), Filamin 7 (amino acids 862-960), Filamin 8 (amino acids 961-1056), Filamin 9 (amino acids 1057-1149), Filamin 10 (amino acids 1150-1244), and Filamin 11 (amino acids 1245-1344)-represent a substantial portion of the repeat architecture. Each repeat adopts a beta-sandwich structure, creating binding surfaces for numerous protein partners.
The arrangement of these repeats enables filamin C to interact simultaneously with multiple binding partners, functioning as a molecular scaffold. Different repeats exhibit specificity for distinct interaction partners, allowing the protein to coordinate diverse cellular processes. The C-terminal repeats mediate protein dimerisation, enabling two filamin C molecules to associate and form functional crosslinks between actin filaments. This modular organisation, with a dedicated actin-binding domain and multiple protein-interaction repeats, is characteristic of the filamin protein family and underlies the protein's ability to integrate structural and signalling functions within muscle cells.
Key variants
Pathogenic variants in FLNC encompass a spectrum of molecular changes that disrupt normal protein function. Missense variants, which alter single amino acids, represent the most common class of pathogenic changes identified in this gene. These substitutions often cluster within the filamin repeat domains and the actin-binding region, reflecting the functional importance of these segments. Truncating variants, including nonsense and frameshift changes, have also been documented and typically result in loss of the C-terminal protein-interaction domains.
The clinical consequences of FLNC variants depend on the location and nature of the molecular change. Some variants appear to act through dominant-negative mechanisms, where the altered protein interferes with the function of the normal protein produced from the unaffected gene copy. Other variants may cause disease through haploinsufficiency, where a single functional gene copy cannot produce sufficient protein to maintain normal muscle structure and function. Research suggests that certain variant locations correlate with specific cardiac or skeletal muscle phenotypes, though considerable clinical variability exists even among individuals carrying the same pathogenic variant.
Founder effects have been observed in some populations, where specific FLNC variants occur at higher frequencies due to shared ancestry. Variant classification relies on multiple lines of evidence, including population frequency data, computational predictions of pathogenicity, functional studies, and clinical observations from affected families. The interpretation of FLNC variants continues to evolve as more data accumulate from clinical and research studies.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.102G>A | p.Trp34Ter | Pathogenic | ★★☆☆ | Hypertrophic cardiomyopathy 26 |
c.1069C>T | p.Gln357Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1092dup | p.Glu365Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1156G>T | p.Glu386Ter | Pathogenic | ★★☆☆ | Primary dilated cardiomyopathy |
c.1444C>T | p.Arg482Ter | Pathogenic | ★★☆☆ | not specified |
c.1537dup | p.Val513fs | Pathogenic | ★★☆☆ | Distal myopathy with posterior leg and anterior hand involvement |
c.1589_1602del | p.Asp530fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1830dup | p.Pro611fs | Pathogenic/Likely pathogenic | ★★☆☆ | Myofibrillar myopathy 5 |
c.1914C>G | p.Tyr638Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1948C>T | p.Arg650Ter | Pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic FLNC variants cause a spectrum of muscle disorders affecting both cardiac and skeletal muscle tissue. The most commonly recognised associations involve various forms of cardiomyopathy, where the heart muscle becomes structurally and functionally abnormal. Individuals with FLNC-related cardiomyopathy may develop dilated cardiomyopathy, characterised by enlargement of the heart chambers and reduced pumping efficiency, or hypertrophic cardiomyopathy, where the heart muscle becomes abnormally thickened. Restrictive cardiomyopathy (familial) represents another manifestation, in which the heart muscle becomes stiff and less able to fill with blood between contractions. Arrhythmogenic cardiomyopathy (which may specifically involve the right ventricle, hence sometimes termed arrhythmogenic right ventricular cardiomyopathy) involves replacement of muscle tissue with fibrous and fatty tissue, predisposing to dangerous heart rhythm disturbances.
Myofibrillar myopathy (filamin C) primarily affects skeletal muscle, causing progressive muscle weakness that typically begins in adulthood. This condition results from disruption of the myofibril structure within muscle fibres, leading to accumulation of abnormal protein aggregates. Some individuals with FLNC variants develop both cardiac and skeletal muscle involvement, reflecting the protein's importance across multiple muscle types. The age of onset, rate of progression, and specific organ systems affected vary considerably, even within families carrying the same pathogenic variant.
Inheritance pattern
Conditions caused by pathogenic FLNC variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
Within the NHS Genomic Medicine Service, FLNC has been evaluated for inclusion in multiple gene panels that guide clinical testing for inherited conditions. The gene holds green (high confidence) status on the Arrhythmogenic right ventricular cardiomyopathy panel (R133), reflecting robust evidence for its role in this cardiac condition. FLNC also appears with green classification on the Dilated and arrhythmogenic cardiomyopathy panel (R132) and the Hypertrophic cardiomyopathy panel (R131), underscoring its association with multiple cardiomyopathy subtypes.
Beyond cardiac panels, FLNC is listed on the Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies panel (R82), also with green status, recognising the gene's role in skeletal muscle disease. The gene also appears on the Paediatric or syndromic cardiomyopathy panel (R135), the Fetal anomalies panel (R21), and the Arthrogryposis panel (R83), all with green classification. This widespread inclusion across multiple NHS panels reflects the diverse clinical presentations associated with FLNC pathogenic variants and ensures that appropriate genetic testing can be accessed through various clinical pathways depending on the presenting features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with FLNC-related cardiomyopathy, general cardiovascular health principles become particularly relevant. Research in broader cardiomyopathy populations suggests that maintaining a healthy body weight, managing blood pressure, and controlling cholesterol levels may help reduce strain on the heart. A balanced diet rich in fruits, vegetables, whole grains, and lean proteins, whilst limiting sodium intake, aligns with general cardiac health recommendations, though no specific dietary pattern has been proven to prevent or reverse FLNC-related cardiac disease.
Physical activity recommendations require careful individualisation based on cardiac function and arrhythmia risk. Whilst moderate exercise can benefit cardiovascular health in the general population, some forms of strenuous or competitive athletics may pose risks for individuals with certain cardiomyopathies. Clinical guidelines typically advise that exercise intensity and type should be discussed with a cardiologist familiar with the individual's specific condition and cardiac imaging findings, as recommendations vary depending on the subtype and severity of cardiomyopathy present.
Alcohol consumption warrants particular consideration, as excessive intake can worsen heart muscle function and may trigger arrhythmias in susceptible individuals. Many cardiologists recommend limiting or avoiding alcohol in patients with cardiomyopathy, though the threshold for safe consumption, if any, depends on individual circumstances. Smoking cessation is universally recommended, as tobacco use adversely affects cardiovascular health through multiple mechanisms.
For those with skeletal muscle involvement, maintaining mobility and muscle strength through appropriate physical therapy may help preserve function, though exercise programmes should be tailored to individual capacity and guided by neuromuscular specialists. Individuals with FLNC variants should discuss lifestyle modifications with their healthcare team to develop personalised recommendations based on their specific clinical manifestations and overall health status.
Supplement considerations
No dietary supplements have been demonstrated to prevent, treat, or modify the progression of FLNC-related muscle disorders. Whilst various micronutrients and compounds are marketed for cardiac or muscle health, robust clinical trial evidence supporting their efficacy in genetically determined cardiomyopathies or myopathies is lacking.
Coenzyme Q10, an antioxidant involved in cellular energy production, has been studied in some forms of cardiomyopathy and muscular dystrophy, but results have been inconsistent and do not establish clear benefits for FLNC-related conditions specifically. Similarly, whilst omega-3 fatty acids have general cardiovascular benefits in some populations, evidence does not support their use as a preventive or therapeutic intervention for inherited cardiomyopathies caused by sarcomeric protein gene variants.
Some individuals with muscle disorders take vitamin D supplements, particularly if blood tests reveal deficiency, as adequate vitamin D status supports general muscle and bone health. However, supplementation beyond correction of documented deficiency has not been shown to improve outcomes in genetic muscle diseases. Creatine supplementation has been explored in various myopathies, though its role in FLNC-related conditions remains uncertain and any use should be discussed with a specialist.
Individuals considering any supplement should consult their cardiologist or neuromuscular specialist before beginning supplementation, as some products may interact with prescribed medications or carry unforeseen risks in the context of specific cardiac or muscle conditions. A healthcare provider familiar with the individual's complete medical picture can offer guidance on whether any particular supplement might be appropriate and can monitor for potential adverse effects.
Frequently asked questions
What does the FLNC gene do?
The FLNC gene provides instructions for making filamin C, a structural protein that organises the internal scaffold of cardiac and skeletal muscle cells. It crosslinks actin filaments and coordinates signalling pathways essential for muscle contraction, development, and repair.
How are FLNC variants inherited?
FLNC-related conditions follow an autosomal dominant pattern of inheritance. This means inheriting one altered copy of the gene from either parent can cause disease, and affected individuals have a 50% chance of passing the variant to each child.
What conditions are associated with FLNC pathogenic variants?
Pathogenic FLNC variants cause various forms of cardiomyopathy, including dilated, hypertrophic, restrictive, and arrhythmogenic subtypes. Some variants also cause myofibrillar myopathy affecting skeletal muscle, and individuals may develop both cardiac and skeletal muscle involvement.
Can FLNC-related cardiomyopathy be treated?
Whilst FLNC-related cardiomyopathy cannot currently be cured, various treatments can manage symptoms and reduce complications. These may include medications to improve heart function, implantable devices to prevent dangerous arrhythmias, and in severe cases, heart transplantation. Treatment is tailored to the individual's specific cardiac manifestations.
Should family members of someone with a FLNC variant be tested?
Cascade testing, where at-risk family members are offered genetic testing, is generally recommended when a pathogenic FLNC variant is identified. Early detection enables surveillance and intervention before symptoms develop, which may improve outcomes, particularly for cardiac manifestations.
Why is FLNC on the ACMG Secondary Findings list?
FLNC appears on the ACMG Secondary Findings list because pathogenic variants in this gene cause actionable cardiac conditions. Early identification allows for monitoring and interventions that can reduce the risk of serious complications such as heart failure and sudden cardiac death, even when genetic testing was performed for unrelated reasons.