ClinVar

Description

The m.9026G>A (p.G167D) variant in MT-ATP6 has been reported in one family to date and features in this family included exercise intolerance, vomiting, and a maternal family history of similar spectrum concerns (PMID: 30763462). Oxidative phosphorylation testing in fibroblasts from the proband were consistent with CV deficiency and all other potential etiologies were reasonably excluded (PP4). Per our literature review and a recently published review, there are no reported de novo occurrences of this variant (PMID: 30763462). This variant segregated with disease in the single reported family as the proband’s healthy brother had undetectable levels of variant in blood and his less severely affected mother (fatigue, migraines, neuropathy) had lower heteroplasmy (4% blood, 8% urine) than the proband (PP1, PMID: 30763462). In silico tools predict this variant to be pathogenic (PP3). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP4, PP1, PP3).