The relationship between MT-ATP8 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 28, 2022. The MT-ATP8 gene encodes the ATP synthase (complex V) subunit 8. Defects of this protein lead to complex V deficiency.
The MT-ATP8 gene was first reported in relation to maternally-inherited primary mitochondrial disease in 2010 (PMID: 20207608). There have been several additional reports linking variants in this gene to various phenotypes associated with primary mitochondrial disease, including before 2010, but there was insufficient evidence to conclude that the features seen in reported individuals were caused by the identified variants (PMIDs: 15452396, 11062027, 28027978, 23735083, 32858252). While various names have been given to the constellation of features seen in those with MT-ATP8-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-ATP8 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants (m.8403T>C, m.8411A>G, m.8424T>C) identified in three probands from three publications (PMIDs: 24153443, 20207608, 32858252). Age of onset varied from birth to the 30s. Features in affected individuals included muscle weakness, wasting, and cramping; dysarthria, headache, periodic paralysis, seizures, mood disorder, neuropathy, pancreatitis, diarrhea, and weight loss. Brain imaging revealed cerebellar atrophy and labs showed elevated lactate. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function (complex V subunit) shared with other genes associated with primary mitochondrial disease, functional alteration in non-patient cells, and model organisms (PMIDs: 33340416, 32858252, 19759059, 22919063).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 28, 2022 (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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