FLNC

filamin C, the group of Filamins

Basic information

Region (hg38): 7:128830406-128859274

Previous symbols: [ "FLN2" ]

Links

ENSG00000128591 ∙ NCBI:2318 ∙ OMIM:102565 ∙ HGNC:3756 ∙ Uniprot:Q14315 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypertrophic cardiomyopathy 26 (Strong), mode of inheritance: AD
• heart conduction disease (Limited), mode of inheritance: AD
• distal myopathy with posterior leg and anterior hand involvement (Supportive), mode of inheritance: AD
• familial isolated restrictive cardiomyopathy (Supportive), mode of inheritance: AD
• myofibrillar myopathy 5 (Supportive), mode of inheritance: AD
• distal myopathy with posterior leg and anterior hand involvement (Moderate), mode of inheritance: AD
• hypertrophic cardiomyopathy 26 (Moderate), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD
• myofibrillar myopathy 5 (Definitive), mode of inheritance: AD
• hypertrophic cardiomyopathy 26 (Strong), mode of inheritance: AD
• myofibrillar myopathy 5 (Strong), mode of inheritance: AD
• myofibrillar myopathy 5 (Definitive), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, familial hypertrophic 26 (Cardiomyopthy, familial restrictive 5); Myopathy, distal, 4; Myopathy, myofibrillar, 5	AD	Cardiovascular	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	Cardiovascular; Musculoskeletal	15929027; 15824355; 19050726; 21620354; 22131542; 22806379; 23109048; 25351925; 26666891

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FLNC gene.

• Cardiovascular phenotype (52 variants)
• Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant (34 variants)
• Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant (27 variants)
• Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26 (25 variants)
• not provided (22 variants)
• Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant;Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement (21 variants)
• Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement (18 variants)
• Dilated Cardiomyopathy, Dominant;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement (16 variants)
• Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant (14 variants)
• Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5 (13 variants)
• Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant (10 variants)
• Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26 (9 variants)
• Primary familial dilated cardiomyopathy (8 variants)
• Hypertrophic cardiomyopathy 26 (8 variants)
• Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement (8 variants)
• Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26 (7 variants)
• Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5 (7 variants)
• Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5 (6 variants)
• Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement (6 variants)
• Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement (5 variants)
• Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26 (4 variants)
• Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5 (4 variants)
• Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant (4 variants)
• Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5 (4 variants)
• Dilated Cardiomyopathy, Dominant;Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5 (4 variants)
• Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant;Hypertrophic cardiomyopathy 26 (3 variants)
• Cardiomyopathy (3 variants)
• Myofibrillar myopathy 5 (3 variants)
• Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant;Hypertrophic cardiomyopathy 26 (3 variants)
• Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant (2 variants)
• 7 conditions (1 variants)
• Restrictive cardiomyopathy (1 variants)
• Myofibrillar myopathy (1 variants)
• Dilated Cardiomyopathy, Dominant (1 variants)
• Spastic ataxia;Cerebellar ataxia (1 variants)
• Distal myopathy with posterior leg and anterior hand involvement (1 variants)
• Primary dilated cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLNC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			30	1056	45	1131
missense	4	13	1851	108	1	1977
nonsense	90	14	4			108
start loss						0
frameshift	198	35	3			236
inframe indel			43			43
splice donor/acceptor (+/-2bp)	7	64	12			83
splice region			98	142	6	246
non coding			13	432	100	545
Total	299	126	1956	1596	146

Highest pathogenic variant AF is 0.00000661

Variants in FLNC

This is a list of pathogenic ClinVar variants found in the FLNC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-128830408-C-A			Benign (Jun 14, 2018)
7-128830428-G-A			Benign (Jun 14, 2018)
7-128830439-A-G			Likely benign (Jul 05, 2018)
7-128830602-G-T		not specified	Likely benign (Mar 27, 2017)
7-128830606-T-TAGCCCCGGCCGCACCCCC		not specified • FLNC-related disorder	Benign/Likely benign (Apr 22, 2020)
7-128830609-C-T			Likely benign (Jun 01, 2020)
7-128830626-G-T		not specified	Benign/Likely benign (Apr 10, 2023)
7-128830636-G-A		Cardiovascular phenotype	Uncertain significance (Jun 09, 2022)
7-128830641-A-G		Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant	Uncertain significance (Apr 04, 2022)
7-128830642-T-C		Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement	Uncertain significance (Sep 05, 2023)
7-128830648-A-G		Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement	Uncertain significance (Jun 19, 2023)
7-128830650-A-G		Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5	Uncertain significance (Oct 28, 2021)
7-128830652-C-A		Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Oct 18, 2023)
7-128830653-G-A		Myofibrillar myopathy 5;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant	Uncertain significance (Jul 19, 2022)
7-128830653-G-C		Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement;Dilated Cardiomyopathy, Dominant;Myofibrillar myopathy 5	Uncertain significance (Jun 20, 2018)
7-128830654-G-A		Cardiovascular phenotype	Likely benign (Nov 19, 2023)
7-128830656-T-G		Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5 • Cardiovascular phenotype	Uncertain significance (Feb 09, 2024)
7-128830658-C-T		Hypertrophic cardiomyopathy 26;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant	Likely benign (Jul 07, 2023)
7-128830659-T-C		Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement • Cardiovascular phenotype	Benign/Likely benign (Jan 21, 2024)
7-128830668-G-A		Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Jan 25, 2024)
7-128830668-G-T		Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26 • Cardiovascular phenotype	Uncertain significance (Feb 18, 2024)
7-128830670-C-A		Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26	Likely benign (Aug 18, 2023)
7-128830670-C-T		Hypertrophic cardiomyopathy 26;Myofibrillar myopathy 5;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement	Likely benign (Jan 17, 2023)
7-128830674-G-A		Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant;Distal myopathy with posterior leg and anterior hand involvement	Uncertain significance (Aug 03, 2018)
7-128830674-G-C		Distal myopathy with posterior leg and anterior hand involvement;Myofibrillar myopathy 5;Hypertrophic cardiomyopathy 26;Dilated Cardiomyopathy, Dominant	Uncertain significance (Mar 19, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLNC	protein_coding	protein_coding	ENST00000325888	48	28898

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000647	125609	0	38	125647	0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.79	1369	1.69e+3	0.809	0.000117	17582
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000237	0.000235
Ashkenazi Jewish	0.000398	0.000397
East Asian	0.000277	0.000273
Finnish	0.00	0.00
European (Non-Finnish)	0.000153	0.000149
Middle Eastern	0.000277	0.000273
South Asian	0.000164	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Focal adhesion - Homo sapiens (human);Salmonella infection - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Focal Adhesion;MAPK Signaling Pathway;Cell-extracellular matrix interactions;Cell junction organization;Cell-Cell communication (Consensus)

Recessive Scores

• pRec: 0.281

Intolerance Scores

• loftool: 0.00661
• rvis_EVS: -3.64
• rvis_percentile_EVS: 0.29

Haploinsufficiency Scores

• pHI: 0.309
• hipred: Y
• hipred_score: 0.723
• ghis: 0.535

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.908

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Flnc
• Phenotype: homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: flnca
• Affected structure: slow muscle cell
• Phenotype tag: abnormal
• Phenotype quality: non-functional

Gene ontology

• Biological process: cell junction assembly;muscle fiber development
• Cellular component: cytoplasm;cytosol;cytoskeleton;plasma membrane;focal adhesion;sarcoplasm;Z disc;sarcolemma;costamere
• Molecular function: protein binding;cytoskeletal protein binding;ankyrin binding;actin filament binding