Cardiomyopathy_Paediatric

Gene: ACTN2

Green List (high evidence)

The ClinGen cardiomyopathy moderate curation was done back in 2018, there have been many new publications since. There is enough evidence suggesting loss of function is a mechanism of disease (along with dominant negative)
gnomAD v2.1: LOEUF=0.24
Cardiac evidence
LoF
At least 11 truncating (1 in last exon), one of which is de novo, loss of function zebrafish model, patient hiPCS cardiomyocytes with a cardiac phenotype
2 - PMID: 34802252 - ACTN2, p.Gln860Ter (last exon) identified homozygous in a individual with cardiomyopathy and atrial fibrillation, had a translplant in her 20s & proband with frameshift ACTN2 exon 8-10 deletion and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The deletion segregated in 6 affected family members. Studied human iPSC-derived cardiomyocytes from both probands. Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins
4 - PMID: 33500567 - significant association between ACTN2 truncating variants and LVNC in a meta-analysis compared to gnomAD. gnomAD count: 13/125,085, gnomAD freq 0.01%, LVNC count: 4/611, LVNC freq: 0.66%, Case excess: 0.65%, p value=1.3E-06, OR 63.4 (20.6–195.0)
variants from this study include PMID: 29447731 - NM_001103.2 p.(Trp303*) in 1 proband and NM_001103.2 p.(Asp196Thrfs*14) in another proband with non-compaction cardiomyopathy. Also 1 proband NCCM with NM_001103.2:c.574C>T p.(Arg192*) and a frameshift SCN5A variant (also reported in PMID: 32445794). Study also includes PMID: 30471092 and PMID: 28798025
1 - PMID: 32973354 - 1 individual with LVNC and 2 affected individuals with HCM with a frameshift ACTN2 exon 3-6 deletion
1 de novo - PMID: 31333075 - Infant with LVNC and requiring transplant with NM_001103.2:c.574C>T p.(Arg192*) de novo, MYLK2 variant inherited from father with trabeculation, & EYA4 variant inherited from unaffected mother. (also reported in PMID: 34540771, 31568572)
1 - PMID: 28436997 - NM_001103.2:c.574C>T p.(Arg192*) identified in a DCM patient
PMID: 22767232 - loss-of-function studies by antisense morpholino technology in zebrafish. Depletion of actn2 did not affect the early steps of sarcomere assembly but reduced cardiac function, primarily characterized as a reduced end-diastolic diameter. The depletion of actn2 also significantly reduced the ventricle chamber size, due to both reduced cardiomyocyte (CM) size and CM number.
1 - SCV001192606.1 - NM_001103.4(ACTN2):c.229G>T (p.Glu77Ter) - at least one individual with DCM submitted by Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare
1 - SCV002058317.1 - NM_001103.4(ACTN2):c.311T>A (p.Leu104Ter) - single heterozygote with Coronary artery atherosclerosis (present) , Left ventricular diastolic dysfunction (present) , Left ventricular hypertrophy (present) , Orthostatic hypotension (present) submitted by 3billion
Missense:
PMID: 36078153 - ACTN2mut c.740C>T p.Thr247Met hiPSC-CMs present hypertrophy, myofibrillar disarray, ACTN2 aggregation, a higher percentage of multinucleation, and activation of both UPS and ALP. It was associated with a marked reduction of sarcomere-associated protein levels and force impairment
PMID: 31956495 - c.1418A>G (p.Tyr473Cys) segregates with left-dominant arrhythmogenic cardiomyopathy in 4 individuals in a single Swiss family. Variant is present in 4 hets in gnomAD v3.1 and absent from v2.1.
PMID: 27287556 - assessed the function of A119T and G111V in in vitro assays. Determined the variants have small effects on structure, function and behaviour (F-actin binding affinity and altered Z-disc localization and dynamics), which may contribute to a mild phenotype for this disease
PMID: 25224718 - a second Australian family with p.(Ala119Thr) segregating diverse cardiac phenotypes including idiopathic ventricular fibrillation, LVNC, and sudden unexplained death. 4 affected individuals and 1 clinically unaffected individual with the variant.
PMID: 25173926 - missense NM_001103.2:c.683T>C p.(Met228Thr) identified in a 4 generation Italian family. 11 individuals with LVH/Arrhythmias/noncompaction with the variant, and additional 3 affected obligate carriers. 4 individuals with noncompaction cardiomyopathy.
PMID: 20022194 - an Australian HCM family with variable phenotypes including syncope, heart failure, and premature sudden death. ACTN2 missense NM_001103.4:c.355G>A p.(Ala119Thr) (absent from gnomAD v2.1 & v3.1) identified in 7 affected individuals and 2 asymptomatic individuals. Variant not present in 5 relatives that screened normal. T495M identified in 2 unrelated HCM probands, and in 1 family member with abnormal echo (but see gnomAD frequency data below). Glu628Gly (absent from gnomAD) identified in a HCM proband, segregated to 1 offspring with abnormal ECG and 1 offspring with normal screening. Glu583Ala (6 alleles in gnomAD v2.1) identified in a HCM proband.
PMID: 17097056 - 3 HCM probands from Mayo clinic with 3 different missense variants, 1 is more common than you would expect for HCM: G111V (absent gnomAD v2.1 & v3.1), T495M (gnomAD v2.1 78 alleles, 1 hom, Euro (NF) AF 0.0004492; gnomAD v3.1 (non-v2) 30 alleles), R759T (absent gnomAD v2.1 & v3.1)

Created: 12 Jul 2023, 6:08 a.m. | Last Modified: 12 Jul 2023, 6:08 a.m.

Panel Version: 0.172

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cardiomyopathy, hypertrophic, 23, with or without LVNC, MIM# 612158

I don't know

Rated Moderate by ClinGen 6 Aug 2018:
Evidence summary per ClinGen: ACTN2 was associated with hypertrophic cardiomyopathy in humans in 2006 (Theis et al, 2006, PMID 17097056) and dilated cardiomyopathy in 2010 (Zimmerman et al, 2010, PMID 20474083). Twelve unique heterozygous variants of unknown significance (11 missense, 1 frameshift), with little to no experimental evidence to support their pathogenicity, have been reported in ACTN2 in humans. Missense variants in this gene segregated with atypical HCM in one family (max LOD 2.8) (Chiu et al, 2010, PMID 20022194), diverse cardiac phenotypes including sudden death, LVNC, DCM, and ventricular fibrillation in a second family (related to the first based on haplotype analysis) (Bagnal et al, 2014, PMID 25224718), and with combinations of HCM, LVNC and arrhythmia in another family (14 segregations) (Girolami et al, 2014, PMID 25173926). The mechanism for disease is unknown. Case-control studies have found no increased frequency of rare ACTN2 variants in individuals with HCM, suggesting that much of the observed variation may be benign (Walsh et al, 2016, PMID 27532257). This gene-disease association is supported by the function of the protein (Bagnal et al, 2014, PMID 25224718), protein interaction with CSRP3 and SCN5A (Louis et al, 2007, PMID 9341203; Ziane et al, 2010, PMID 19943616; Vafiadaki et al, 2014, PMID 24860983), expression of the gene product (alpha actinin-2) in heart (Beggs et al, 1992, 1339456; Haywood et al, 2016, PMID 27287556), and rescue of a DCM phenotype in a zebrafish model (Gupta et al, 2012, PMID 22253474). In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. Based on curated literature, this gene can cause seemingly isolated left ventricular hypertrophy. Given the lack of constraint of ACTN2, classification of variants in this gene should be considered with care. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 7, 2017. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism underlying the disease entities: (1) Cardiomyopathy, dilated, 1AA, with or without LVNC (MIM: 612158) and (2) Cardiomyopathy, hypertrophic, 23, with or without LVNC (MIM: 612158). Note that both of these disease entities have the same MIM numbers, suggesting that they are part of the same condition. ACTN2 was curated for intrinsic cardiomyopathy based upon the variable cardiac presentations, including cardiomyopathies and arrhythmias, observed in large families with ACTN2 variants. For clinical management, all of the phenotypes are cardiovascular, and individuals should be monitored appropriately. Therefore, all of the disease entities have been lumped into one disease entity, Intrinsic cardiomyopathy.

Created: 19 Jun 2020, 10:59 a.m. | Last Modified: 19 Jun 2020, 10:59 a.m.

Panel Version: 0.28

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hypertrophic cardiomyopathy; left ventricular non compaction; dilated cardiomyopathy

Publications

• PMID: 30681346