ClinVar

Description

The m.9155A>G (p.Q210R) variant in MT-ATP6 has been reported in three unrelated individuals in the literature (PMIDs: 34961688, 27966441, 27450679) and has been reported to have been seen by experts on this panel in an additional three unrelated individuals. Heteroplasmy levels were variable in affected individuals as were mitochondrial disease features, although diabetes and deafness were reported in several individuals (PS4_moderate; PMIDs: 34961688, 27966441, 27450679). The variant occurred in de novo in one of the cases reported by an expert on this panel and in one of the cases reported in the literature (PS2_moderate; PMID: 27450679). There are no large families reported in the medical 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 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS2_moderate, PS4_moderate, PM2_supporting, PP3.