Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies
Gene: ACTN2
Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next major review.Created: 16 Apr 2023, 8:38 p.m. | Last Modified: 16 Apr 2023, 8:38 p.m.
Panel Version: 4.7
Comment on mode of inheritance: There are at least 8 unrelated cases with monoallelic inheritance reported in literature.
Although there are three unrelated Japanese cases with biallelic inheritance reported in PMID:34471957, all of them were identified with the same homozygous variant.
'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' has currently been chosen as the MOI and it will be reviewed when more cases are reported with biallelic inheritance. Hence, 'watchlist_moi' tag has been added.Created: 16 Apr 2023, 8:36 p.m. | Last Modified: 26 Apr 2023, 10:08 a.m.
Panel Version: 4.11
PMID:30900782 reported four unrelated families segregating with heterozygous variants (three Spanish families: c.1459T>C/ p.Cys487Arg; one Swedish family: c.392T>C/ p.Leu131Pro) in ACTN2 gene and presenting with distal myopathy.
PMID:34170073 reported a Chinese family with frameshift variant (c.2504delT/ p.Phe835Serfs*66) segregating with distal myopathy, where the proband was diagnosed with distal myopathy with multi‐minicores on muscle biopsy. In addition, in vitro assays demonstrated p. Phe835Serfs*66 and p. Leu131Pro variants resulted in protein aggregation, whereas p.Cys487Arg and p.Leu727Arg are similar to wild type.
PMID:34386585 reported three individuals from two families with heterozygous variants (2 individuals from family : c.2567del/ p.Pro856Argfs*45; family 2: c.2558del/ p.Glu853Glyfs*48) and presenting with distal myopathy and facial weakness.
PMID:36116040 reported two individuals from a Spanish family with distal myopathy and they were identified with the splice site variant c.1840‐2A>T.
PMID:34471957 reported three unrelated Japanese cases with distal myopathy with the same homozygous missense variant (c.1439A>G/ p.Asn480Ser). Functional studies with in vitro assays demonstrate the variant does not interfere with protein dimerisation and cellular localisation.Created: 16 Apr 2023, 8:29 p.m. | Last Modified: 16 Apr 2023, 8:29 p.m.
Panel Version: 4.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Myopathy, distal, 6, adult onset, OMIM:618655
Publications
Multiple individuals from multiple families reported suggesting ACTN2 as both, monoallelic and biallelic cause of muscular dysctrophy.
Sources: LiteratureCreated: 28 Nov 2021, 1:43 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Muscular dystrophy; hyperCKemia
Publications
Tag watchlist_moi tag was added to gene: ACTN2.
Tag Q2_23_promote_green tag was added to gene: ACTN2.
Gene: actn2 has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: ACTN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ACTN2 were changed from Myopathy, distal, 6, adult onset, OMIM:618655 to Myopathy, distal, 6, adult onset, OMIM:618655
Phenotypes for gene: ACTN2 were changed from Muscular dystrophy; hyperCKemia to Myopathy, distal, 6, adult onset, OMIM:618655
Publications for gene: ACTN2 were set to 30900782; 34170073; 34386585; 34471957; 36116040
Publications for gene: ACTN2 were set to 30900782; 34170073; 34386585; 34471957; 36116040
Publications for gene: ACTN2 were set to PMID: 34471957; 30701273; 30900782
gene: ACTN2 was added gene: ACTN2 was added to Limb girdle muscular dystrophy. Sources: Literature Mode of inheritance for gene: ACTN2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ACTN2 were set to PMID: 34471957; 30701273; 30900782 Phenotypes for gene: ACTN2 were set to Muscular dystrophy; hyperCKemia Penetrance for gene: ACTN2 were set to unknown Review for gene: ACTN2 was set to GREEN