TIMMDC1

Inheritance Pattern: AR

Disease ID:MONDO:0032634

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032634

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0032634

Submitter: Illumina

The TIMMDC1 gene is located on chromosome 3 at 3q13.33 and encodes the translocase of inner mitochondrial membrane domain containing 1 protein. This protein functions as a membrane-embedded assembly factor for complex I of the mitochondrial respiratory chain. TIMMDC1 was first reported in relation to autosomal recessive mitochondrial complex I deficiency, nuclear type in 2017 (28604674: Kremer et al. 2017). To date, a single deep intronic variant that disrupts splicing has been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. The deep intronic variant was reported in a homozygous state in three unrelated individuals of differing ethnicities in a single publication (28604674: Kremer et al. 2017). The variant also segregated with the disease in two additional family members. Loss of function is the mechanism of disease. This gene-disease relationship is also supported by expression data, a role in complex I assembly/function shared with other genes associated with mitochondrial disease, rescue of impaired complex I assembly in patient cells by the expression of WT TIMMDC1, and in vitro evidence that TIMMDC1 depletion in human cells impairs mitochondrial function, including a specific loss of complex I activity, reduced oxygen consumption, disrupted mitochondrial morphology, and reduced complex I assembly (24344204: Guarani et al. 2014; 25613900: Uhlén et al. 2015; 28604674: Kremer et al. 2017). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TIMMDC1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 30, 2021. The TIMMDC1 gene encodes translocase of inner mitochondrial membrane domain-containing protein 1, a NADH:ubiquinone oxidoreductase (complex I) assembly factor. The TIMMDC1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2017 (PMID: 28604674). There were other individuals in this paper reported to have Leigh syndrome spectrum, however not enough details were provided to confirm this diagnosis. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 28604674). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression data, functional alteration in non-patient cells, and rescue in patient cells (PMIDs: 24344204, 25613900, 28604674). In summary, there is limited evidence to support this gene-disease relationship. Although the total score (7) falls in the moderate range, only one case with Leigh syndrome spectrum has been reported and confirmed, therefore this gene-disease association can only reach a limited classification at this time. 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 June 30, 2021 (SOP Version 7).