NDUFC2

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFC2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 18, 2023. The *NDUFC2* gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit C2, which also plays a role in complex I assembly. Defects of this protein lead to complex I deficiency. The first and only report of *NDUFC2* in relation to autosomal recessive primary mitochondrial disease was in 2020 (PMID:32969598) in two unrelated probands with Leigh syndrome spectrum (LSS). While various names could be given to the constellation of features seen in those with *NDUFC2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFC2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFC2* was first curated by this GCEP for its association with LSS on November 23, 2020 (SOP Version 7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two variants (homozygous missense and homozygous stop-loss) identified in two cases in one publication (PMID: 32969598). This gene-disease association is also supported by functional implication its known biochemical function (PMID: 27509854) and by complexome profiling in patient cells (PMID: 32969598). In summary, there is moderate evidence to support the relationship between *NDUFC2* and primary mitochondrial disease. 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 December 18, 2023 (SOP Version 9).

Inheritance Pattern: Unknown

Disease ID:MONDO:0030902

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0030902

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFC2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 23, 2020. The NDUFC2 gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit C2, which also plays a role in complex I assembly. Defects of this protein lead to complex I deficiency. The NDUFC2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2020 (PMID: 32969598). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two variants identified in two cases in one publication (PMID: 32969598). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction, functional alteration in non-patient cells, and functional alteration in patient cells (PMIDs: 27509854, 27626371, 32969598). In summary, there is moderate 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 23, 2020 (SOP Version 7).