ACTA1

protein-coding

actin alpha 1, skeletal muscle, the group of Actins

Gene summary

The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]

Previous symbols:

ACTA

MANE transcript

NM_001100.4

Inheritance

AR, SD, AD

ClinVar variants

P:251U:195B:92

Top phenotype

Congenital myopathy 2C, severe infantile, autosomal dominant; Myopathy, congenital, with fiber-type disproportion 1; Congenital myopathy 2A, severe infantile or typical, autosomal dominant; Myopathy, scapuloperoneal; Congenital myopathy 2A, typical, autosomal dominant; Congenital myopathy 2B, severe infantile, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr1:229,430,365-229,434,104

External References & Databases

Ensembl (ENSG00000143632)

Transcript & Mutation Effects

hg38 • Region Span ~3.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

severe congenital nemaline myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015735

Submitter: Orphanet

congenital myopathy with excess of thin filamentsDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0020342

Submitter: Illumina

rigid spine syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019951

Submitter: Orphanet

zebra body myopathySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0019949

Submitter: Orphanet

congenital myopathy 2a, typical, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008070

Submitter: Labcorp Genetics (formerly Invitae)

progressive scapulohumeroperoneal distal myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014800

Submitter: Orphanet

congenital myopathy 2a, typical, autosomal dominantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008070

Submitter: Labcorp Genetics (formerly Invitae)

childhood-onset nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015738

Submitter: Orphanet

congenital myopathy 2c, severe infantile, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859523

Submitter: Labcorp Genetics (formerly Invitae)

alpha-actinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100084

Submitter: ClinGen

Actinopathy is a musculoskeletal system disorder that covers a wide spectrum of phenotypes and is caused by pathogenic variants in the skeletal muscle α-actin gene, *ACTA1*. These variants lead to a variety of overlapping adult onset and congenital myopathies characterized by muscle weakness, hypotonia, myopathic facies, respiratory dysfunction, and rarely cardiac involvement. While nemaline myopathy is the most common presentation, several other myopathies have been reported in association with *ACTA1* mutations. Specific skeletal muscle structural lesions visible on muscle biopsy include actin accumulations, nemaline and intranuclear bodies, fiber-type disproportion, cores, caps, dystrophic features and zebra bodies. Disorders associated with *ACTA1* pathogenic variants can have autosomal dominant (90%) or recessive (10%) inheritance. Per criteria outlined by the Lumping and Splitting Working Group, we found differences in molecular mechanism (dominant negative vs. recessive loss of function) and inheritance pattern actinopathy was split into dominant and recessive curations. The dominant curation includes phenotypes across a spectrum of disease including typical and severe infantile congenital myopathy as well as scapulohumeroperoneal myopathy (OMIM 616852, 161800, 620278). *ACTA1* was first reported in relation to dominant actinopathy in 1999 (Nowak KJ, et al., 1999, PMID: 10508519). At least 190 unique variants (predominantly missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 21 probands in 7 publications (PMIDs: 10508519, 25938801, 15468086, 15520409, 20303757, 25747004, 15198992). Variants in this gene segregated with disease in at least 25 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. In vitro studies suggest that abnormal folding, altered polymerization and aggregation of mutant actin isoforms are common properties of dominant *ACTA1* variants. Some of these effects are mutation-specific, and likely result in variations in the severity of muscle weakness seen in individual patients and to the common pathological hallmarks in skeletal muscle. This gene disease association is supported by its biochemical function in muscle contraction (PMID: 21314430), its skeletal muscle specific expression (PMID: 1743394), the functional alteration of contractility in patient cells (PMID: 29328520) and two knock-in mouse models (PMIDs: 21303860, 22067542) that recapitulate human disease. In summary *ACTA1* is definitively associated with dominant inheritance of actinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

congenital fiber-type disproportion myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009711

Submitter: Orphanet

typical nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015737

Submitter: Orphanet

alpha-actinopathySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0100084

Submitter: PanelApp Australia

congenital myopathy 2a, typical, autosomal dominantDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0008070

Submitter: Ambry Genetics

intermediate nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015736

Submitter: Orphanet

congenital myopathy 2a, typical, autosomal dominantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008070

Submitter: G2P

alpha-actinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100084

Submitter: ClinGen

Actinopathy is a musculoskeletal system disorder that covers a wide spectrum of phenotypes and is caused by pathogenic variants in the skeletal muscle α-actin gene, *ACTA1*. These variants lead to a variety of overlapping adult onset and congenital myopathies characterized by muscle weakness, hypotonia, myopathic facies, respiratory dysfunction, and rarely cardiac involvement. While nemaline myopathy is the most common presentation, several other myopathies have been reported in association with *ACTA1* mutations. Specific skeletal muscle structural lesions visible on muscle biopsy include actin accumulations, nemaline and intranuclear bodies, fiber-type disproportion, cores, caps, dystrophic features and zebra bodies. Disorders associated with *ACTA1* pathogenic variants can have autosomal dominant (90%) or recessive (10%) inheritance. Per criteria outlined by the Lumping and Splitting Working Group, we found differences in molecular mechanism (dominant negative vs. recessive loss of function) and inheritance pattern actinopathy was split into dominant and recessive curations. *ACTA1* was first reported in relation to recessive actinopathy in 1999 (Nowak KJ, et al., 1999, PMID: 10508519). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Biallelic loss of function variants (splicing, frameshift, nonsense, and missense) in this gene have been reported in at least 7 probands in 5 publications (PMIDs: 10508519, 12921789, 15236405, 17187373, 24447884). Variants in this gene segregated with disease in at least 4 additional family members. More evidence may be available in the literature, but the maximum score for genetic evidence has been reached. This gene disease association is supported by its biochemical function in muscle contraction (PMID: 21314430), its skeletal muscle specific expression (PMID: 1743394), and a null mouse model (PMID: 12138199) that partially recapitulates human disease. In summary *ACTA1* is definitively associated with recessive inheritance of actinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 4952447; 9185179; 10508519; 11333380; 11558787; 15236405; 15520409; 15468086; 16427282; 17187373; 19553116; 22442437; 25182138; 25938801; 27242277

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACTA1 variants in ClinVar

34 Conditions Cataloged

Actin accumulation myopathyTotal: 471

not providedTotal: 161

Alpha-actinopathyTotal: 55

not specifiedTotal: 52

ACTA1-related disorderTotal: 39

Congenital myopathy with fiber type disproportionTotal: 30

Congenital myopathy 2c, severe infantile, autosomal dominantTotal: 22

Progressive scapulohumeroperoneal distal myopathyTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001100.4. 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			7 clinvar	92 clinvar		99
missense	84 clinvar	130 clinvar	181 clinvar			395
nonsense	6 clinvar	5 clinvar				11
start loss			3 clinvar			3
frameshift	8 clinvar	9 clinvar	3 clinvar			20
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	1 clinvar			10
Total	101	150	195	92	0	538

Highest pathogenic variant AF is 0.000021706719

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001100.4	RefSeq	NP_001091.1	6	MANE Select
ENST00000366684.7	Ensembl	ENSP00000355645.3	6	MANE Select
ENST00000366683.4	Ensembl	ENSP00000355644.4	6	Standard
ENST00000366683.5	Ensembl	ENSP00000355644.4	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
acta1b	Danio rerio	Structure: skeletal muscle cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

acta1b

Danio rerio

Structure: skeletal muscle cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Myometrial Relaxation and Contraction Pathways
Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation
Association Between Physico-Chemical Features and Toxicity Associated Pathways
Striated Muscle Contraction
erk and pi-3 kinase are necessary for collagen binding in corneal epithelia

Biological Process

muscle contraction
response to mechanical stimulus
response to extracellular stimulus
response to lithium ion
positive regulation of gene expression

Molecular Function

structural constituent of cytoskeleton
protein binding
ATP binding
myosin binding
ADP binding

Cellular Component

stress fiber
extracellular space
cytosol
striated muscle thin filament
actin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366684
Coding exons: 6
Length: 2854
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.53	55	261	0.211	0.0000176	2498
Missense (PolyPhen)		22	126.98	0.17325		1140
Synonymous	1.11	102	117	0.870	0.00000992	744
Loss of Function	0.934	11	14.9	0.739	6.45e-7	161

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00020	0.00018	rare
South Asian	0.00042	0.00039	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.;
Disease: DISEASE: Nemaline myopathy 3 (NEM3) [MIM:161800]: A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. {ECO:0000269|PubMed:10508519, ECO:0000269|PubMed:11166164, ECO:0000269|PubMed:11333380, ECO:0000269|PubMed:15198992, ECO:0000269|PubMed:15236405, ECO:0000269|PubMed:15336687, ECO:0000269|PubMed:15520409, ECO:0000269|PubMed:16427282, ECO:0000269|PubMed:16945537, ECO:0000269|PubMed:17705262, ECO:0000269|PubMed:22442437, ECO:0000269|PubMed:23650303, ECO:0000269|PubMed:25938801}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, actin, congenital, with excess of thin myofilaments (MPCETM) [MIM:161800]: A congenital muscular disorder characterized at histological level by areas of sarcoplasm devoid of normal myofibrils and mitochondria, and replaced with dense masses of thin filaments. Central cores, rods, ragged red fibers, and necrosis are absent. {ECO:0000269|PubMed:10508519}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, congenital, with fiber-type disproportion (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. {ECO:0000269|PubMed:15468086, ECO:0000269|PubMed:17387733}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, scapulohumeroperoneal (SHPM) [MIM:616852]: An autosomal dominant muscular disorder characterized by progressive muscle weakness with initial scapulo-humeral-peroneal and distal distribution. Over time, muscle weakness progresses to proximal muscle groups. Clinical characteristics include scapular winging, mild lower facial weakness, foot drop due to foot eversion and dorsiflexion weakness, and selective muscle atrophy. Age at onset and disease progression are variable. {ECO:0000269|PubMed:25938801}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.937

Intolerance Scores

LoFtool: 0.244
RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.824

Gene Damage Prediction

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