ClinVar

Description

The m.9205_9206delTA (p.Ter227M) variant in MT-ATP6 has been reported in two unrelated probands with features of primary mitochondrial disease (neonatal lactic acidosis, failure to thrive, spasticity, microcephaly, developmental delay; PS4_supporting; PMIDs: 8739943, 15265003). The variant was de novo in one of these individuals (absent in mother and maternal grandmother's lymphocytes via PCR-SSCP; PM6_supporting; PMID: 8739943). In the other family, this variant segregated with disease in two unaffected family members as they had lower levels of the variant, however the unaffected mother’s heteroplasmy level was still fairly high at >90% (PMID: 15265003). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids or single fiber studies reported on this variant. The loss residue removes the termination codon for MT-ATP6 and sets MT-CO3 immediately in frame. This results in decreased steady state level of RNA14, the ATPase 8- and 6-encoding bi-cistronic mRNA unit, causing dysregulation of mRNA stability (PM4, PMID: 12915481). 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 the functional evidence showing destabilization of the RNA. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PM4, PS4_supporting.