TIMM22

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0030017

Submitter: Ambry Genetics

Inheritance Pattern: Unknown

Disease ID:MONDO:0030017

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0030017

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TIMM22* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 29, 2024. The *TIMM22* gene encodes translocase of inner mitochondrial membrane 22, an essential component of the TIM22 complex. This complex acts as the voltage-activated and signal-gated twin pore and mediates the import and insertion of multipass proteins into the inner mitochondrial membrane. The first and only report of *TIMM22* in relation to autosomal recessive primary mitochondrial disease was in 2018 (PMID: 30452684). *TIMM22* has been associated with a single disease entity to date, combined oxidative phosphorylation deficiency 43 [OMIM# 618851]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique variants (one stop gain variant although nonsense mediated decay is not expected as the premature stop occurs within first 100 base pairs; one missense variant) identified in one case from one publication (PMID: 30452684). Of note, the missense variant is present in population databases including in the homozygous state, so it is hypothesized this is a hypomorphic allele given the extensive functional validation performed in fibroblasts from the single case report. The single reported case had intrauterine growth restriction, low birth weight and length, reduced spontaneous movements, feeding difficulty, gastroesophageal reflux with vomiting, delayed myelination, and elevated blood lactate and creatine kinase. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416). 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 July 29, 2024 (SOP Version 10).