The relationship between ATP5MD (up until recently referred to as USMG5 and/or DAPIT) and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2020. The ATP5MD gene encodes a subunit of the mitochondrial ATP synthase, also known as complex V of the oxidative phosphorylation system. Defects of this protein lead to a reduction of ATP synthesis.
The ATP5MD gene has been reported in relation to autosomal recessive Leigh syndrome spectrum in a single publication in 2018 (PMID: 29917077). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in three cases in one publication (PMID: 29917077). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression data, functional alteration in patient cells, functional alteration in non-patient cells, rescue in patient cells, and a model system (PMIDs: 18853439, 30240627, 21345788, 31127358, 29917077).
In summary, there is moderate 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 13, 2020 (SOP Version 7).
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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