ClinVar

Description

The m.8528T>C variant in MT-ATP6 (p.M1T), MT-ATP8 (p.W55R) has been reported in seven unrelated individuals with primary mitochondrial disease with lactic acidosis, hyperammonemia, and hypertrophic cardiomyopathy. The levels of the variant in affected individuals ranged from 15% to homoplasmic (PS4_moderate; PMIDs: 30642647, 33180048, 19188198). There are no reported de novo occurrences of this variant to our knowledge. The variant segregated with disease manifestations in three families. In the first report (PMID: 19188198), two healthy family members had lower levels of the variant than the proband (proband had variant at 92-98% in 5 tissues; unaffected mother had the variant at 15-25%; unaffected aunt at 0%). In the second report (PMID: 26803244), the proband had the variant present at 90% heteroplasmy in heart and 86% in fibroblasts at autopsy; the healthy mother had the variant present at 1.4% in fibroblasts. In the third report (PMID: 33180048), the proband was homoplasmic for the variant and the variant was heteroplasmic in his mother who had mild features (short stature, frequent migraines; 82% in blood, 89% in urine, and 59% in saliva; PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.63 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, 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 two gene products are affected by this variant and the consistent biochemical phenotype reported. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PM2_supporting, PP3.