Submission Details

The relationship between MPV17 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 21, 2022. The MPV17 gene encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis and the maintenance of the mitochondrial DNA (mtDNA).

While various names have been given to the constellation of features seen in those with MPV17-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MPV17 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

The MPV17 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2006 (PMID: 16582910) in an infant from a consanguineous family with liver failure and severe depletion of liver mtDNA. Subsequent publications have reported over eighty families with MPV17 variants. Most cases are characterised by an early onset, severe and often fatal liver failure with liver specific mtDNA depletion, although variability in the age of onset and severity has been reported. The Navajo founder variant, c.149A>G (p.Arg50Gln), has been associated with a phenotype spectrum of disease, even within families. Affected individuals homozygous for c.149A>G (p.Arg50Gln) may have either an infant or childhood onset of disease characterised by a spectrum of severe to moderate liver disease and progressive neuropathy. Additional features may include corneal ulcerations, acral mutilation, poor somatic development with sexual infantilism, and serious systemic infections. More than 100 variants have been associated with disease, including missense, nonsense, frameshift, indels, and splice variant, all of which are predicted or have been shown to lead to a loss of MPV17 function.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included fourteen unique variants reported in fourteen cases from seven publications (PMIDs: 16582910, 29282788, 1690939, 29318572, 26437932, 30298599, 22508001). Variants included three frameshift, two nonsense, two splice variants and six missense variants. Two founder variants were curated: c.149A>G (p.Arg50Gln) in the Navajo population and c.106C>T (p.Gln36Ter) in the Black South African population. More evidence is available in the literature, but cases scored reached a maximum of 12 points. This gene-disease relationship is also supported by a biochemical function (mtDNA maintenance) shared with other genes associated with primary mitochondrial disease. Mouse and zebrafish models recapitulate aspects of the liver phenotype associated with disease, together with altered mtDNA depletion and mitochondrial dysfunction (PMIDs: 1696177, 26760297, 24247928, 30833296).

In summary, there is definitive evidence to support the relationship between MPV17 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 July 21, 2022 (SOP Version 9).