Limb-Girdle Muscular Dystrophy and Distal Myopathy
Gene: ACTN2
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: LiteratureCreated: 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
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
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).
Gene: actn2 has been classified as Green List (High Evidence).
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