ClinVar

Description

The m.9191T>C (p.L222P) variant in MT-ATP6 has been reported once in the literature (PMID: 16217706, patient 2) in an individual with Leigh syndrome (94% heteroplasmy in muscle and 90% in fibroblasts; only testing done was MT-ATP6 and MT-ATP8 sequencing). This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant occurred de novo in this individual (absent in blood from mother and sister; PM6_supporting, PMID: 16217706). There are no large families reported in the literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Yeast model showed (1) failure to grow on glycerol (indicating at least an 80% reduction in ATP synthase activity/function), (2) 67-85% decrease in oxygen consumption, (3) <10% of control ATP synthesis, and (4) impaired ATPase assembly (PS3_supporting, PMID: 24316278). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given consistent functional evidence of severe deleterious effect and rare nature of the variant, as well as being absent in healthy cohorts even at low heteroplasmy levels. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on January 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM6_supporting, PP3.