| Variant | Genes / protein change | Genetic state | Onset / cardiac phenotype | Extracardiac / biochemical features | Functional consequence | Evidence / source |
|---|---|---|---|---|---|---|
| m.8528T>C | Overlapping **MT-ATP8/MT-ATP6** variant; affects A6L **p.Trp55Arg** and ATP6 start codon/subunit a **p.Met1Thr** | Usually **high heteroplasmy >90%**; one reported patient had **59% in blood** | **Directly associated with infantile HCM**: prenatal to 5 months; **hypertrophic cardiomyopathy / biventricular hypertrophy**, heart failure; some cases rapidly progressive and fatal in months | Hypotonia, failure to thrive, feeding difficulties, metabolic crises, 3-methylglutaconic aciduria, hyperketonemia; reported arrhythmia/WPW, pulmonary arterial hypertension, LV noncompaction, anemia, thrombocytopenia, myopathy/progressive weakness | Marked reduction in synthesis of **both ATPase 6 and 8**, reduced complex V levels/assembly-stability, decreased ATP synthesis; review states loss of subunit a is primary driver | Core infantile HCM allele; summarized from 2024 review and cited primary infantile cardiomyopathy reports (pqac-00000004, pqac-00000002, pqac-00000006) |
| m.8529G>A | Overlapping **MT-ATP8/MT-ATP6** variant; primarily affects **A6L p.Trp55Ter**; nearby allelic comparator | Reported **high heteroplasmy >90%** | **Not a direct infantile HCM allele in available evidence**; later onset (~4 years) with HCM reported in one patient, milder than m.8528T>C | Neuropathy, ataxia, ophthalmoplegia, psychomotor retardation | Decreased ATP synthase stability; unlike m.8528T>C, mainly affects **A6L** rather than causing loss of subunit a | Useful allelic comparison showing overlapping-region variants can differ markedly in severity and age at onset (pqac-00000007, pqac-00000001) |
| m.8993T>G | **MT-ATP6**; ATP6 **p.Leu156Arg** | Often **high heteroplasmy**; >90% strongly associated with severe Leigh/MILS spectrum | **Broader MT-ATP6 disease context**; cardiomyopathy can occur, but available evidence does **not** support it as a specific core allele for infantile HCM | Leigh syndrome/MILS, lactic acidosis, developmental delay/regression, seizures, brainstem dysfunction, peripheral neuropathy, optic atrophy; low citrulline in broader MT-ATP6 disease | Impaired ATP synthase assembly, decreased ATP synthesis, abnormal membrane potential; severity tracks with heteroplasmy | Major disease-context allele; common in cohorts, including infantile-onset MT-ATP6/8 disease, but not specific for infantile HCM (pqac-00000013, pqac-00000014, pqac-00000008) |
| m.8993T>C | **MT-ATP6**; same codon as m.8993T>G with different substitution | Heteroplasmic; higher loads linked to more severe disease | **Broader MT-ATP6 disease context**; review notes cardiomyopathy has been linked, but phenotype is predominantly neurodegenerative and often later than overlapping-region infantile HCM | NARP/Leigh spectrum, variable neurologic disease; biomarkers in MT-ATP6/8 cohorts include lactate elevation, alanine elevation, reduced citrulline | Complex V dysfunction with variable biochemical findings; no single universal assay abnormality | Included to frame broader genotype-phenotype spectrum without over-attributing infantile HCM (pqac-00000002, pqac-00000012, pqac-00000015) |
| m.9176T>G / m.9176T>C | **MT-ATP6** codon 217 variants | Heteroplasmic to homoplasmic; severe disease more likely at high mutant load | **Broader MT-ATP6 disease context**; can be associated with Leigh-spectrum disease and cardiomyopathy/non-neurologic manifestations, but not established here as a defining infantile HCM allele | Newborn-screened MT-ATP6 cases with low citrulline and/or elevated C5-OH included **m.9176T>G**; neurologic phenotypes range from asymptomatic to hypertonia/intellectual disability; hypertrophic cardiomyopathy recognized among MT-ATP6 manifestations overall | ATP synthase dysfunction; therapeutic research includes mitoTALEN targeting of **m.9176T>C** in murine oocytes in experimental prevention studies | Important contextual alleles for diagnosis/screening and experimental therapy, not the core infantile HCM genotype in available evidence (pqac-00000011, pqac-00000009, pqac-00000001) |


*Table: This table summarizes the strongest available genotype-phenotype evidence for MT-ATP6/MT-ATP8-related infantile hypertrophic cardiomyopathy, centered on the overlapping-region m.8528T>C allele. It also places neighboring and common MT-ATP6 alleles in context while distinguishing direct infantile HCM evidence from broader mitochondrial disease associations.*