NDUFV2

Inheritance Pattern: AR

Disease ID:MONDO:0032612

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFV2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. The *NDUFV2* gene encodes the NADH:ubiquinone oxidoreductase (complex I) flavoprotein 2, a core subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency. *NDUFV2* was first reported in relation to autosomal recessive primary mitochondrial disease in 2003 (PMID: 12754703), in a proband with hypertrophic cardiomyopathy, encephalopathy, feeding difficulty, and growth failure who died at three months of age. While various names could be given to the constellation of features seen in those with *NDUFV2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFV2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFV2* was previously curated by this GCEP on November 20, 2019 (SOP Version 7) as having a Limited association with Leigh Syndrome Spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS. Evidence supporting the gene-disease relationship between *NDUFV2* and primary mitochondrial disease includes case-level data and experimental data. This curation includes nine unique variants in ten probands from nine publications (PMIDs: 12754703, 19167255, 26008862, 33811136, 34405929, 28429146, 30369941, 34276053, 30831263). Variant types included five missense, one frameshift, one stop-gain, one intragenic deletion and one recurrent splice region variant (NM_021074.5:c.120+5_120+8del). Affected individuals present with a broad phenotypic spectrum of generally severe disease which includes LSS. Clinical features include developmental regression, seizures, progressive spasticity, microcephaly, hypotonia, hypertrophic cardiomyopathy, optic atrophy, feeding difficulty, and failure to thrive. The age of onset ranges from birth to early infancy. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and a C. elegans model system (PMIDs: 33340416. 19672299). In summary, there is Definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 4, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFV2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2019. The NDUFV2 gene encodes the NADH:ubiquinone oxidoreductase (complex I) flavoprotein 2, a core subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency. The NDUFV2 gene has been reported in relation to autosomal recessive Leigh syndrome spectrum in a single publication in 2011 (PMID: 26008862). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 26008862). 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 interactions (PMID: 27509854). In addition, variants in NDUFV2 have been associated with other phenotypes outside the scope of the Leigh syndrome spectrum gene-disease curation. In summary, there is limited evidence to support a 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 November 20, 2019 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0032612

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0032612

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0032612

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet