FLNC
protein-codingfilamin C, the group of Filamins
Gene summary
This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]
- FLN2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0000992
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0018943
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014883
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018943
Submitter: ClinGen
Non-loss of function variation of FLNC results in the development of myofibrillar myopathy 5 presenting with a combination and isolated skeletal and cardiac features. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism and phenotypic variability. Loss of function variation causes weakening of myocyte adhesion and is implicated in arrhythmogenic cardiomyopathy and dilated cardiomyopathy without musculoskeletal abnormalities (Verdonschot 2020, PMID 32112656). Conversely, the mechanism of non-loss of function variation for FLNC-induced myopathy is attributed to the aggregation of FLNC and FLNC-binding proteins in muscle and the sarcomere (Furst 2013, PMID 23109048). Therefore, we have split the molecular mechanism, curating only non-loss of function variation for the disease entity [Myopathy, myofibrillar, 5] (OMIM: 609524). Over 22 probands in 9 publications have been published (Vorgerd 2005, PMID 15929027; Kley 2007, PMID 18055494; Kley 2012, PMID 22961544; Shatunov 2009, PMID 19050726; Laun 2010, PMID 20417099; Avila-Smirnow 2012, PMID 27633507; Roldán-Sevilla 2019, PMID 30919686; Gaudreault 2023, PMID 36864778;; Bermúdez-Jiménez 2023, PMID 35952944). There were 16 unique heterozygous variants (12 missense, 1 in-frame deletion, 1 in-frame indel, 1 duplication, and 1 termination in the last exon). One variant (p.Trp2710Ter) was seen in 36 affected individuals across six families and represents a founder effect. Of note, FLNC has a pseudogene located 53.6kb downstream from the functional FLNC gene, and exons 46, 47, and 48 are 98% homologous in the functional and pseudogene (Odgerel 2010, PMID: 20578970). The gene-disease relationship is also supported by expression studies, protein interaction studies, and model systems (Xie 1998, PMID 979101; Furst 2013, PMID 23109048; van der Ven 2000, PMID 11038172; Gonzalez-Morales 2017 2017, PMID 28732005; Labeit 2006, PMID 16949617; Chevessier 2015, PMID 29859533; Kiselev 2018, PMID 29859533; Ruparelia 2016, PMID 26969713; Agarwal 2012, PMID 34405687), reaching the maximum points for experimental evidence. In summary, there is definitive evidence supporting the relationship between FLNC non-loss of function variation and autosomal dominant myofibrillar myopathy 5. This has been repeatedly demonstrated in research and clinical settings and upheld over time. This gene-disease pair was originally evaluated as definitive by the ClinGen Hypertrophic Cardiomyopathy GCEP on December 12th, 2017. As a result of this reevaluation, the classification has remained the same; however, the molecular mechanism has been split to include only non-loss of function variation approved on October 26, 2023, by the Hereditary Cardiovascular Disease GCEP.
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: ClinGen
FLNC was originally evaluated for DCM by ClinGen DCM GCEP on October 9, 2020. Evidence of the association of this gene with DCM was re-evaluated on 4/09/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. FLNC was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2014 (Deo et al., 2014, PMID:(25633252). Deo et al. identified a splice site variant in one proband with DCM, but did not include details regarding genotype-phenotype correlation, family history, segregation data, or experimental evidence to support the pathogenicity of the variant, and therefore did not contribute to the genetic evidence score. However, since 2014, additional human genetic evidence supporting this gene-disease relationship has been reported and includes case-level data, segregation data, and case-control data. Numerous variants (missense, frameshift, truncating) have been reported in humans with isolated DCM (Ortiz-Genga et al., 2016, PMID: 27908349; Janin et al., 2017, PMID: 28436997; Sveinbjornsson et al., 2018, PMID: 30354339; others). In addition, this gene-disease assertion is supported by animal models. Begay et al. (2016, PMID: 28008423) generated a morpholino (MO) induced flnb knockdown in zebrafish. Zebrafish embryos injected with flncb MO showed more frequent cardiac phenotypes and reduced survival. The transgenic GFP-injected flncbþ p53 MO zebrafish embryos at 48 and 72 hpf demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. Nearly all of the injected embryos displayed varying degrees of reduced blood circulation, accompanied by an increase in retrograde blood flow and overall weaker contractility. Further, Fujita et al. (2012, PMID: 22020047) analyzed the effect of a nonsense FLNC variant found in medaka fish mutant "zacro". Mutants were characterized by an abnormally enlarged heart with a gradually reduced blood flow. At stage 28, prior to the heart looping, zac mutants showed blood congestion in the ventricle along with pericardial edema. Ruptures in the myocardium layer were detected in the zac mutants at stage 27, especially in the dorsal-right myocardium of the ventricle. As the endocardium was intact in zac mutants, the blood accumulation might have been caused by ineffective contraction of the torn myocardium. FLNC has also been curated by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel for myofibrillar myopathy (Definitive, 12/12/2017). In summary, FLNC is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 9, 2020 (SOP Version 7). This written summary was updated on 04/09/2025 and approved by the DCM GCEP on 05/30/2025.
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012289
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014883
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013550
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013550
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013550
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012289
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019150
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012289
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal
Intervention: Cardiovascular
Rationale: Individuals (including with Distal myopathy or Myofibrillar myopathy) have been described with cardiomyopathy, and surveillance (eg, including echocardiography an electrocardiography) may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FLNC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001458.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 32 | 1469 | 20 | 1521 | ||
| missense | 7 | 40 | 2663 | 424 | 17 | 3151 |
| nonsense | 115 | 44 | 6 | 165 | ||
| start loss | 0 | |||||
| frameshift | 265 | 97 | 13 | 375 | ||
| splice donor/acceptor (+/-2bp) | 20 | 103 | 15 | 138 | ||
| Total | 407 | 284 | 2729 | 1893 | 37 | 5350 |
Highest pathogenic variant AF is 0.000019710908
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001449.3 | 48 | MANE Select | |
| Ensembl | ENSP00000327145.8 | 48 | MANE Select | |
| RefSeq | NP_001120959.1 | 47 | Standard | |
| Ensembl | ENSP00000344002.6 | 47 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| flnca | Danio rerio | Structure: slow muscle cell Quality: non-functional abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Focal adhesion - Homo sapiens (human)
- Salmonella infection - Homo sapiens (human)
- MAPK signaling pathway - Homo sapiens (human)
- Proteoglycans in cancer - Homo sapiens (human)
- Focal Adhesion
Biological Process
- cell junction assembly
- muscle fiber development
Molecular Function
- protein binding
- cytoskeletal protein binding
- ankyrin binding
- actin filament binding
Cellular Component
- cytoplasm
- cytosol
- cytoskeleton
- plasma membrane
- focal adhesion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000325888
- Coding exons
- 48
- Length
- 28898
- Individuals with no LoFs
- 125609
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 38
- Defined
- 125647
- p
- 0.000151
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.79 | 1369 | 1.69e+3 | 0.809 | 0.000117 | 17582 |
| Missense (PolyPhen) | 603 | 860.05 | 0.70112 | 9087 | ||
| Synonymous | -0.679 | 766 | 742 | 1.03 | 0.0000579 | 5651 |
| Loss of Function | 7.96 | 18 | 107 | 0.169 | 0.00000543 | 1284 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000064 | 0.000062 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.00028 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Muscle-specific filamin, which plays a central role in muscle cells, probably by functioning as a large actin-cross- linking protein. May be involved in reorganizing the actin cytoskeleton in response to signaling events, and may also display structural functions at the Z lines in muscle cells. Critical for normal myogenesis and for maintaining the structural integrity of the muscle fibers.;
- Disease
- DISEASE: Myopathy, myofibrillar, 5 (MFM5) [MIM:609524]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM5 is characterized by onset in adulthood, clinical features of a limb-girdle myopathy, and focal myofibrillar destruction. {ECO:0000269|PubMed:15929027}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, distal, 4 (MPD4) [MIM:614065]: A slowly progressive muscular disorder characterized by distal muscle weakness and atrophy affecting the upper and lower limbs. Onset occurs around the third to fourth decades of life, and patients remain ambulatory even after long disease duration. Muscle biopsy shows non-specific changes with no evidence of rods, necrosis, or inflammation. {ECO:0000269|PubMed:21620354}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 26 (CMH26) [MIM:617047]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:25351925}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial restrictive 5 (RCM5) [MIM:617047]: A heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function. {ECO:0000269|PubMed:26666891}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.281
Intolerance Scores
- LoFtool
- 0.00661
- RVIS EVS
- -3.64
- RVIS percentile EVS
- 0.29
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.908
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |