SUCLA2

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0012791

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SUCLA2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 11, 2019. 25 articles were reviewed. SUCLA2 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2005 (Epeleg et al., PMID 10545952). More than 50 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands with Leigh syndrome spectrum in 9 different publications (PMID 17301081, 23010432, 10545952, 23759946, 26952923, 27913098, 17287286, 26475597, 25582465). This gene-disease association is further supported by the function of the gene product, protein interaction, expression, and studies in cell lines. In summary, there is definitive evidence to support the relationship between SUCLA2 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association, thus reaching a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 11, 2019 (SOP Version 6).

Inheritance Pattern: AR

Disease ID:MONDO:0012791

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SUCLA2* and *SUCLA2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 17, 2024. The *SUCLA2* gene encodes succinate-CoA ligase ADP-forming subunit beta, an ATP-specific succinyl-CoA synthetase that functions in the tricarboxylic acid (TCA) cycle to catalyze the reversible synthesis of succinate and adenosine triphosphate (ATP). It is also thought to have a role in mitochondrial DNA (mtDNA) maintenance, possibly by stabilizing the nucleoside diphosphate kinase. The *SUCLA2* gene was first reported in relation to autosomal recessive *SUCLA2*-related primary mitochondrial disease in 2005 (PMID: 10545952). *SUCLA2* has been associated with one disease entity to date; mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) [OMIM# 612073]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *SUCLA2*-related primary mitochondrial disease. Of note, *SUCLA2* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on February 11, 2019 (SOP v6), with a final classification of Definitive. This current curation for the association with *SUCLA2*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 unique variants (seven missense, one complex rearrangement, one frameshift, and one splice site, c.534+1G>A, that is a founder variant in Faroe Islands, Denmark) identified in 10 unrelated cases from nine publications (PMIDs: 17301081, 23010432, 23759946, 27913098, 26475597, 25582465, 15877282, 26952923, 17287286). Disease onset is early in life. Clinical features in affected individuals include LSS, developmental delay and regression, encephalopathy, myopathy, choreoathetosis, dystonia, seizures, ptosis, sensorineural hearing loss, feeding difficulty, failure to thrive, and elevated lactate and methylmalonic acid. 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: 23385875), functional alteration in non-patient cells (PMID: 28769029), and non-human animal models (PMID: 24271779). In summary, there is definitive evidence to support the relationship between *SUCLA2* and autosomal recessive *SUCLA2*-related 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 June 17, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0012791

Submitter: Labcorp Genetics (formerly Invitae)