Submission Details

The PRKACG gene, encoding the Protein Kinase CAMP-Activated Catalytic Subunit Gamma, was first associated with autosomal recessive platelet-type bleeding disorder 19 in 2014 by Manchev VT et al. (PMID: 25061177). This gene-disease relationship is supported by both genetic and experimental evidence. Case-level genetic evidence from the aforementioned study includes the identification of two siblings with a homozygous missense variant in PRKACG (c.222C>G, p.Ile74Met). Additionally, the proband had a missense variant in the GNE gene, which at the time was not associated with thrombocytopenia, leaving the GNE variant's role in the condition unexplored. Therefore, this case has not been classified as providing genetic-level evidence. Experimental evidence highlights the Functional Alteration in patient cells, where Filamin A (FLNa) was significantly reduced in mature megakaryocytes (MKs) and platelets of patients carrying the homozygous mutation in PRKACG. This suggests that PRKACG is crucial for FLNa phosphorylation. Furthermore, patients exhibited elevated cAMP levels, three to five times higher than controls, hinting at compromised protein kinase A (PKA) activity due to the PRKACG mutation.Rescue experiments in patient cells demonstrated that overexpressing wild-type PRKACG in MKs from patients with the PRKACG homozygous variant notably improved proplatelet (PPT) formation, in contrast to the null effects seen with the mutant PRKACG. The introduction of wild-type PRKACG also resulted in a significant reduction in the size of platelet-like structures along the PPTs, underscoring the disruption of the PKA pathway by the PRKACG mutation as a causative factor for thrombocytopenia. In summary, there is disputed evidence to support this gene-disease relationship. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on DATE (SOP Version 10).