Submission Details

ACTB was first reported in relation to ACTB-associated syndromic thrombocytopenia (ACTB-AST) in 2018 (Latham et al., PMID:30315159). The ACTB gene encodes beta-actin which plays a role in cellular processes, including cell migration and division, cell shape, and the regulation of gene expression. ACTB-associated syndromic thrombocytopenia is an autosomal dominant syndromic disorder characterized by developmental delay, mild intellectual disability, microcephaly, facial abnormalities, and thrombocytopenia with platelet anisotropy and enlarged platelets. ACTB is also associated with Baraitser-Winter syndrome 1, Becker nevus syndrome, developmental malformation deafness/dystonia syndrome, and intellectual disability. ACTB-AST is curated as a unique disease, and to date, only variants in the 5th and 6th exon (pen/ultimate exons) of ACTB have been implicated in ACTB-associated syndromic thrombocytopenia. Evidence supporting this gene-disease curation includes case level data and experimental data.

Summary of Case Level Data (5.8 points): Eight unique variants (missense, amino acid deletions, and frameshift) have been reported in humans, including instances of de novo variation. Variants in this gene have been reported in at least 8 probands in 5 publications (Latham et al., 2018 PMID: 30315159; Nunoi et al., 1999 PMID: 10411937; Fouassier et al., 2023 PMID: 36564926; Atmar et al., 2022 PMID: 35572556; Marconi et al., 2023 PMID: 36519321). Variants in this gene segregated with disease in 2 additional family members.

Summary of Experimental Evidence (2.5 points): The gene-disease relationship is supported by expression, biochemical function, and functional alteration in patient cell experiments (Latham et al., PMID:30315159).

In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

This gene-disease pair was originally evaluated by the ClinGen Hemostasis and Thrombosis (H/T) Gene Curation Expert Panel on 11/24/2021. It was reevaluated on 05/25/2022 and additional evidence was added (Greve et al., 2022 PMID: 35313204). On June 3rd, 2024, the gene-disease classification was re-evaluated again, and although additional scoreable genetic evidence has emerged, the classification did not change.

Of note, there are two published cases in which variants in the 4th exon of ACTB are seen in individuals with a phenotype that partially overlaps the phenotype seen in individuals with ACTB-AST. These variants are included in the curation, but are not scored at this time (Sandestig et al., 2019 PMID: 30733661; Megy et al., 2021 PMID: 34355501).