The relationship between TIMMDC1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 22, 2024. TIMMDC1 encodes translocase of inner mitochondrial membrane domain-containing protein 1, a mitochondrial respiratory chain complex I assembly factor.
TIMMDC1 was first reported in relation to autosomal recessive mitochondrial disease in 2017 (PMID: 28604674). While various names have been given to the constellation of features seen in those with TIMMDC1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TIMMDC1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, TIMMDC1 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on June 30, 2021 (SOP v7), with a final classification of Limited. This current curation for the association with primary mitochondrial disease includes the single case included in the LSS curation.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants (one recurrent deep intronic variant (c.597-1340A>G), one missense variant, one nonsense variant) in six probands from three publications (PMIDs: 28604674, 36349561, 33278652). Clinical features in affected individuals include Leigh syndrome spectrum, movement disorders, microcephaly, and corpus callosum agenesis.
The mechanism of disease is loss of function This gene-disease association is also supported by its known biochemical functional, functional studies in non-patient cells, and rescue studies in patient cells (PMIDs: 28797839, 24344204, 24191001, 28604674).
In summary, there is definitive evidence to support the relationship between TIMMDC1 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 22, 2024 (SOP Version 10).
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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