Submission Details

The relationship between TMEM70 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 16, 2022. The TMEM70 gene encodes a mitochondrial respiratory chain complex V assembly factor that likely works in complex I assembly (PMIDs: 32275929, 33753518), as well.

The TMEM70 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18953340). While various names have been given to the constellation of features seen in those with TMEM70-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TMEM70 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (two splice site, two nonsense, one frameshift) identified in eight individuals from two publications (PMIDs: 18953340, 21147908). More evidence is available in the literature but the maximum score for genetic evidence (12 pts.) has been reached. The majority of cases reported had nonsense or splice variants. Affected individuals typically presented in utero to shortly after birth and outcomes varied from death in the first days of life to still being alive at the time of report in their 20s. Affected individuals had variable features including microcephaly, developmental delay, episodic encephalopathy with febrile illness, hypotonia, hypertrophic cardiomyopathy, persistent pulmonary arterial hypertension, hepatopathy, short stature, and cataract; at least one report included an individual with normal cognitive abilities. Brain imaging in affected individuals ranged from normal to hypoplastic corpus callosum, cerebellar atrophy, and cortical atrophy; and metabolic screening labs variably showed lactic acidosis, increased CSF lactate, and lactate excretion in urine; metabolic acidosis; hyperammonemia; and 3MGA. Other features seen in affected individuals include oligohydramnios, hypospadias, cryptorchidism, and dysmorphic features (high forehead, low set ears, long philtrum, broad nasal bridge, thin lips). The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration in patient cells, rescue in patient cells, knock-out mouse model, and rescue in a knock-out rat model (PMIDs: 24740313, 21945727, 28173120, 35203486).

In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 16, 2022 (SOP Version 8).