Limb-Girdle Muscular Dystrophy and Distal Myopathy

Gene: ACTN2

Green List (high evidence)

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)

At least 8 families segregating variants with dominant distal myopathy and 1 variant reported with recessive inheritance. Some functional evidence suggesting protein aggregation is the mechanism of disease
4 fams - PMID: 30900782 - 3 Spanish families segregating c.1459T>C p.(Cys487Arg) with distal myopathy & 1 Swedish family segregated c.392T>C p.(Leu131Pro)
1 fam - PMID: 34170073 - a frameshift c.2504delT, p. Phe835Serfs*66 resulting in C-terminal extension segregating with distal myopathy in a Chinese family. The proband was diagnosed with distal myopathy with multi‐minicores on muscle biopsy. In vitro assays demonstrated p. Phe835Serfs*66 and p. Leu131Pro resulted in protein aggregation, whereas p.C487R and p.L727R were similar to WT
1 fam - PMID: 36116040 - 2 individuals with distal myopathy in a Spanish family with the splice site variant c.1840‐2A>T, shown with RNA studies to lead to an in-frame deletion (r.1840_1878del p.(Val614_Gln626del)).
0 - PMID: 34471957 - 3 apparently unrelated Japanese probands with distal myopathy with the same homozygous missense - c.1439A>G p.(Asn480Ser). The variant appears to be associated with a recessive inheritance pattern but there is a suggestion of semidominance in one of the families. In vitro assays demonstrate the variant does not interfere with protein dimerisation and cellular localisation.
2 fams - PMID: 34386585 - c.2567del p.Pro856Argfs*45 and c.2558del p.Glu853Glyfs*48 resulting in C-terminal elongation identified in 3 individuals with distal myopathy from 2 families.
Sources: Literature
Created: 13 Apr 2023, 4:14 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myopathy, distal, 6, adult onset MIM#618655

Publications

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

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

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
  • Expert Review Amber
  • Victorian Clinical Genetics Services
Phenotypes
  • Myopathy, distal, 6, adult onset MIM#618655
OMIM
102573
Clinvar variants
Variants in ACTN2
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

13 Apr 2023, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

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

13 Apr 2023, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

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

13 Apr 2023, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set mode of pathogenicity

Bryony Thompson (Royal Melbourne Hospital)

gene: ACTN2 was added gene: ACTN2 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature Mode of inheritance for gene: ACTN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTN2 were set to 30900782; 34170073; 36116040; 34471957; 34386585 Phenotypes for gene: ACTN2 were set to Myopathy, distal, 6, adult onset MIM#618655 Mode of pathogenicity for gene: ACTN2 was set to Other Review for gene: ACTN2 was set to GREEN gene: ACTN2 was marked as current diagnostic