TMEM126A

Inheritance Pattern: AR

Disease ID:MONDO:0013069

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0003608

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013069

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013069

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013069

Submitter: ClinGen

*TMEM126A* was first reported in relation to autosomal recessive *TMEM126A*-related optic atrophy with or without extraocular features (MONDO:0013069), also called optic atrophy (OPA7 type), in 2009 (Hanein S et al., PMID:19327736). Individuals with the disease present with bilateral optic atrophy, temporal disc pallor and poor visual acuity in childhood, usually in early childhood. Some cases have also reported color vision defects, sensorineural hearing loss, and/or neuropathy. Individuals reported in the literature have experienced both the gradual and sudden onset of symptoms, always in the first two decades of life. This curation includes one nonsense variant, two missense variants, a splice variant and a frameshift variant that have been reported in 10 probands across 6 publications (PMID: 19327736, PMID: 20405026, PMID: 22815638, PMID: 31119195, PMID: 30961538, PMID: 36071901). Notably, the nonsense variant, c.163C>T;p.Arg55Ter, has been reported in at least six of North African consanguineous families and makes up for a large proportion of the cases both in the literature and in this curation. Functional studies are not reported on this variant but the premature stop codon occurs in exon 3/5 upstream of a known alternative start codon of a protein coding transcript (ENST00000528105.5) (PMID: 19327736, PMID: 20405026, PMID: 22815638). One proband of Korean descent has also been published with the p.Arg55Ter variant in trans with another presumed null *TMEM126A* variant. More evidence may be available in the literature, but the maximum score for genetic evidence has been exceeded. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by *in vitro* functional assays and a cell culture model (PMID: 23500070, PMID: 33882309, PMID: 33879611). *In vitro* functional analysis reveals that TMEM126A is an integral mitochondrial protein anchored to the mitochondrial inner membrane (PMID: 23500070) and that it functions as an assembly factor for mitochondrial respiratory complex I (PMID: 33882309). Given the relationship between mitochondrial function and optic atrophy, this serves as evidence that a disruption of the biochemical function of TMEM126A is consistent with the phenotype reported in OPA7 type patients. As an assembly factor, TMEM126A associates with the ND4 subunit encoded by the gene *mt-ND4*, which has been curated by the ClinGen Mitochondrial Diseases Gene Curation Expert panel to have a definitive relationship with mitochondrial disease which can present with optic atrophy. HEK293T cells with *TMEM126A* deleted via genome editing show complex I deficiency (PMID: 33879611), matching one of the *TMEM126A*:p.Arg55Ter probands (PMID:19327736). This complex I deficiency was rescued in the cell model by the introduction of a construct expressing *TMEM126A* (PMID: 33879611). In summary, there is definitive evidence supporting the relationship between *TMEM126A* and autosomal recessive* TMEM126A*-related optic atrophy with or without extraocular features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology GCEP on the meeting date September 19, 2024 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0013069

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TMEM126A* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 22, 2024. The *TMEM126A* gene encodes an inner mitochondrial membrane protein that is an important complex I assembly factor in ND4-module assembly. *TMEM126A* was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19327736). While various names have been given to the constellation of features seen in those with *TMEM126A*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TMEM126A* 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 variants (one nonsense, two missense, one splice site, one frameshift) in 11 probands from seven publications (PMIDs: 19327736, 20405026, 22815638, 30961538, 31119195, 32855858, 36071901). Optic atrophy was the most common clinical feature in affected individuals. Additional clinical features noted include hearing loss, migraines, hypertrophic cardiomyopathy, myoclonic jerks, and brisk reflexes. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of *TMEM126A* in complex I assembly, functional alteration in non-patient cells, and rescue studies (PMIDs: 33882309, 33879611). In summary, there is definitive evidence to support the relationship between *TMEM126A* 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 August 22, 2024 (SOP Version 10).