The relationship between C12orf65 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The C12orf65 gene encodes an important mitochondrial translation release factor that functions in releasing newly synthesized peptides from the mitochondrial ribosome.
The C12orf65 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2010 (PMID: 20598281). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in six cases from five publications (PMIDs: 20598281, 24284555, 27858754, 25995486, 26380172). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, functional alteration in non-patient cells, and rescue in patient cells (PMIDs: 27977873, 18853439, 20598281, 22821833, 27858754, 26380172).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 9, 2019 (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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