Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: ACTN2

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 10:47 a.m. | Last Modified: 11 Dec 2025, 10:47 a.m.

Panel Version: 5.24

Green List (high evidence)

Additional recessive variant reported (PMID: 38311799)

p.Arg506Gly reported in seven patients from five families with muscle weakness. All families of Palestinian descent suggesting a potential founder variant

Created: 2 Mar 2025, 10:33 a.m. | Last Modified: 2 Mar 2025, 10:33 a.m.

Panel Version: 4.40

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID: 38311799

Green List (high evidence)

Comment on mode of inheritance: As reviewed by Cassandra Smith, PMID:3831179 reported a different biallelic variant (p.Arg506Gly) in seven patients from five families of Palestinia decent, all presenting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. This variant is suggested to be a possible founder variant, which was confirmed through haplotype analysis in two families.

The MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as there is sufficient evidence available for the association of biallelic variants with the phenotype.

Created: 25 Apr 2025, 11:08 a.m. | Last Modified: 25 Apr 2025, 11:08 a.m.

Panel Version: 4.41

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 5 Dec 2024, 5:12 p.m. | Last Modified: 5 Dec 2024, 5:12 p.m.

Panel Version: 4.40

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
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Myopathy, distal, 6, adult onset, OMIM:618655

Publications

• 30900782
• 34170073
• 34386585
• 34471957
• 36116040
• 3831179

Green List (high evidence)

Multiple individuals from multiple families reported suggesting ACTN2 as both, monoallelic and biallelic cause of muscular dysctrophy.
Sources: Literature

Created: 28 Nov 2021, 1:43 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Muscular dystrophy; hyperCKemia

Publications

• PMID: 34471957
• 30701273
• 30900782, 38311799