An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Gene

Area of Science:

• Genetics and Molecular Biology
• Human Genetics
• Rare Diseases

Background:

• The ACTA1 gene encodes skeletal muscle alpha-actin, a key component of the sarcomeric thin filament.
• ACTA1 is one of six highly conserved actin isoforms, all linked to human diseases.
• The number of reported pathogenic ACTA1 variants has significantly increased since 1999.

Purpose of the Study:

• To update the catalog of ACTA1 variants and pathogenic classifications.
• To propose ACTA1-specific guidelines for variant interpretation.
• To review ACTA1-associated phenotypes, genotype-phenotype correlations, and therapeutic strategies.

Main Methods:

• Comprehensive literature review and database analysis (LOVD, HGMD, ClinVar).
• Application of modified ACMG guidelines for variant classification.
• Analysis of genotype-phenotype correlations and existing animal models.

Main Results:

• A total of 607 ACTA1 variants are reported, with 343 previously classified as pathogenic/likely pathogenic (P/LP).
• Proposed ACTA1-specific criteria identified 447 P/LP variants.
• The number of associated phenotypes has expanded to 20, including nemaline myopathy, cardiomyopathy, and distal myopathy.

Conclusions:

• This study provides an updated and comprehensive resource for ACTA1 variant interpretation and research.
• Refined variant classification criteria enhance diagnostic accuracy for ACTA1-related disorders.
• Further research into genotype-phenotype correlations and preclinical treatments is warranted for ACTA1 diseases.