The relationship between AGK and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 6, 2023. The AGK gene encodes mitochondrial acylglycerol kinase, a lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to generate lysophosphatidic acid and phosphatidic acid, respectively, in the inner mitochondrial membrane (IMM). Independent of its kinase activity, this protein also functions as a member of the TIM22 complex, which is required for the import of multi-pass transmembrane proteins into the IMM.
The AGK gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22284826), in several individuals with variable congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis (features seen in Sengers syndrome). While various names have been given to the constellation of features seen in those with AGK-related disease, including Sengers syndrome, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the AGK phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting the gene-disease relationship between AGK and primary mitochondrial disease includes case-level data and experimental data. This curation includes eight variants (four nonsense, four frameshift) in five probands in three publications (PMIDs: 22284826, 25208612, 28868593) although additional cases have been reported in the medical literature. Affected individuals had bilateral cataracts, hypertrophic cardiomyopathy, skeletal myopathy, motor delay, hypotonia, and feeding difficulties. Metabolic screening labs showed lactic acidosis. Loss of function is implicated as the mechanism of disease.
This gene-disease relationship is also supported by known biochemical function and in vitro functional assays demonstrating reduced rates of mitochondrial import due to variants in AGK (PMIDs: 33340416, 28712726).
In summary, there is definitive evidence to support the relationship between AGK and autosomal recessive primary mitochondrial disease. More than three years have elapsed since the first assertion of this gene-disease relationship, and no contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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