Mendeliome
Gene: ACTN2 Green List (high evidence)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
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
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 behaviourCreated: 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
Gene: actn2 has been classified as Green List (High Evidence).
Mode of inheritance for gene: ACTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: actn2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ACTN2 were changed from 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 to 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 for gene: ACTN2 were set to PMID: 34802252; 27287556
Phenotypes for gene: ACTN2 were changed from to 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 for gene: ACTN2 were set to
Gene: actn2 has been classified as Green List (High Evidence).
Mode of inheritance for gene: ACTN2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
gene: ACTN2 was added gene: ACTN2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ACTN2 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.