Submission Details

ACTN2 was first reported in association with autosomal dominant hypertrophic cardiomyopathy in humans in 2006 (Theis et al, 2006, PMID 17097056), dilated cardiomyopathy in 2010 (Zimmerman et al, 2010, PMID 20474083), arrhythmias in 2010 (Chiu et al, 2010, PMID 20022194), left ventricular noncompaction in 2014 (Bagnall et al, 2014, PMID 25224718), restrictive cardiomyopathy in 2016 (Kostareva et al, 2016, PMID 27662471), and left-dominant arrhythmogenic cardiomyopathy in 2020 (Good et al, 2020, PMID 31956495). Cardiac phenotypes are associated with both gain and loss of function ACTN2 variants and do not always fit well into classical cardiomyopathy diagnosis. Individuals can show variable combinations of hypertrophy, dilatation, hyper/hypo contractility, and arrhythmias – where the phenotype can vary between individuals in the same family. A study found that patients with ACTN2 presented with varying degrees and types of arrhythmias, including left bundle branch block, atypical flutter, paroxysmal atrial fibrillation or supraventricular tachycardia, as well as atrial, ventricular, or supraventricular premature beats (Ranta-aho et al, 2022, PMID 36116040).

In 2019, variants in ACTN2 were also reported in association with skeletal muscle myopathies (Savarese et al., PMID 30900782; Lornage et al., PMID 30701273). Clinical features reported in individuals with ACTN2-related skeletal myopathy include progressive distal and/or proximal muscle weakness, gait disturbance, muscle atrophy, and elevated creatine kinase (Iruzubieta et al., 2025, PMID 39812845). Inoue et al. (2021) (PMID 34471957) also report a homozygous missense variant in 4 patients from 3 unrelated families with muscle weakness and signs of muscle pathology, only 1 of whom had cardiac features. In addition, Lindholm et al. (2021) (PMID 34802252) report a homozygous premature truncating variant in a patient with cardiac disease. Respiratory insufficiency, facial weakness, contractures, and loss of ambulation have also been reported in more severe cases. Disease onset varies from early neonatal onset to adulthood. Signs on muscle pathology vary but may include fibre size variation, internalized nuclei, myofibrillar disorganization, type 1 fibre predominance, small cores, and other signs of structural disorganization. Cardiac involvement has been reported in a minority of cases. ACTN2 variants reported in association with skeletal myopathy include missense, in frame deletion, canonical splice, and C-terminal frameshift variants that result in protein extension (PMID 30900782, 30701273, 39812845; Ranta-Aho et al, 2024, PMID 39095936). Lornage et al. (2019) (PMID 30701273) created zebrafish expressing a mutant form of ACTN2 with a patient-identified missense variant, which showed locomotion defects and disordered skeletal muscle architecture. Mice expressing the same variant also showed abnormal Z-line organization in skeletal muscle as well as muscle weakness. A skeletal muscle case from 2024 (Donkervoort et al, 2024, PMID 38311799), included a recurring homozygous missense variant in ACTN2, this variant causes a recessive myopathy, and patients presented with asymmetric, progressive, proximal and distal lower extremity weakness. Another skeletal muscle case from 2019 (Savarese et al, 2019, PMID 30900782) showed 4 different families where 3 Spanish families presented with a heterozygous ACTN2 missense variant, and 1 Swedish family presented with a different heterozygous ACTN2 missense variant. The evidence for the gene disease relationship for ACTN2 suggests an autosomal dominant pattern of inheritance but there are some cases of recessive inheritance. The disease mechanism is currently unclear and may be variant-specific since some variants have been shown to result in protein aggregation while others do not have this effect (PMID 39095936). However, gain of function or dominant-negative effects are most likely; haploinsufficiency is not an established mechanism for ACTN2-related skeletal myopathy.

This gene is thus associated with a phenotypic spectrum of cardiomyopathies, arrhythmias, and skeletal muscle myopathies. There is currently insufficient evidence to split these presentations based on mode of inheritance, phenotype, or disease mechanism. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, all disease entities have been lumped into one inclusive disease entity, which is now being called ACTN2-related cardiac and skeletal myopathy. The inheritance pattern is primarily autosomal dominant, though at least three cases with homozygous variants have been reported (Lindholm et al, 2021, PMID 30701273; Inoue et al, 2021, PMID 34471957; Donkervoort et al, 2024, PMID 38311799).

In summary, there is definitive evidence to support the relationship between ACTN2 and ACTN2-related cardiac and skeletal myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Based on curated literature, this gene can cause seemingly isolated left ventricular hypertrophy. This classification of ACTN2 for intrinsic cardiomyopathy (HCM and DCM) was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on April 10, 2018. It was reevaluated on May 10, 2023, and expanded to include LVNC, RCM, and ACM. As a result of this re-evaluation, the classification changed from moderate to definitive due to new evidence in the literature. This current curation was done on December 11, 2024, and expanded to include skeletal muscle myopathies in the phenotypic spectrum associated with variation in ACTN2.