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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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