Mendeliome
Gene: ACTN2

ACTN2 (actinin alpha 2)
EnsemblGeneIds (GRCh38): ENSG00000077522
EnsemblGeneIds (GRCh37): ENSG00000077522
OMIM: 102573, Gene2Phenotype
ACTN2 is in 8 panels

3 reviews

Bryony Thompson (Royal Melbourne Hospital)

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)

ACTN2-related myopathy reviewed in PMID: 36116040. > 3 families. Loss of function doesn’t appear to be the mechanism of disease for ACTN2-related myopathy. The spectrum of variants includes missense, in-frame splice aberrations, and frameshift that are in the NMD exclusion zone.
Created: 18 Oct 2022, 7:08 a.m. | Last Modified: 18 Oct 2022, 7:08 a.m.

Panel Version: 1.414

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
intrinsic cardiomyopathy MONDO:0000591

Publications

Created: 18 Oct 2022, 7:08 a.m.
Last Modified: 18 Oct 2022, 7:08 a.m.
Panel version: 1.414

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

I don't know

Note association with cardiomyopathy has been rated as MODERATE by ClinGen.
Created: 22 Mar 2022, 8:52 a.m. | Last Modified: 22 Mar 2022, 8:52 a.m.

Panel Version: 0.11748

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Created: 22 Mar 2022, 8:52 a.m.
Last Modified: 22 Mar 2022, 8:52 a.m.
Panel version: 0.11748

Elena Savva (Victorian Clinical Genetics Services)

Green List (high evidence)

Established gene-disease association

Mechanism unclear, both pathogenic and VUS NMD PTCs reported.
PMID: 34802252: Demonstrates that an inframe deletion (exons 8-10) can incorporate into sarcomeres. Strongly suggests DN as a mechanism.
PMID: 27287556: missenses have reduced F-actin binding affinity, and affect Z-disc localization and dynamic behaviour
Created: 22 Mar 2022, 2:27 a.m. | Last Modified: 22 Mar 2022, 2:27 a.m.

Panel Version: 0.11717

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Myopathy, distal, 6, adult onset MIM#618655; Cardiomyopathy, hypertrophic, 23, with or without LVNC MIM#612158; Cardiomyopathy, dilated, 1AA, with or without LVNC MIM#612158; Myopathy, congenital with structured cores and Z-line abnormalities MIM#618654

Publications

PMID: 34802252
27287556

Created: 22 Mar 2022, 2:27 a.m.
Last Modified: 22 Mar 2022, 2:27 a.m.
Panel version: 0.11717

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
Victorian Clinical Genetics Services

Phenotypes

Myopathy, distal, 6, adult onset MIM#618655
Cardiomyopathy, hypertrophic, 23, with or without LVNC MIM#612158
Cardiomyopathy, dilated, 1AA, with or without LVNC MIM#612158
Myopathy, congenital with structured cores and Z-line abnormalities MIM#618654

OMIM

102573

Clinvar variants

Variants in ACTN2

Penetrance

None

Publications

PMID: 34802252
27287556

Panels with this gene

History Filter Activity

12 Jul 2023, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: actn2 has been classified as Green List (High Evidence).

22 Mar 2022, Gel status: 2

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: ACTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

22 Mar 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: actn2 has been classified as Amber List (Moderate Evidence).

22 Mar 2022, Gel status: 3