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A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans

Alexandre BolzeiD, Fernando Luis MendeziD, Simon WhiteiD, Francisco TanudjajaiD, Magnus Isaksson, Ruomu Jiang, Andrew Dei Rossi, Elizabeth T. CirulliiD, Misha D. RashkiniD, William J. Metcalf, Joseph J. GrzymskiiD, William LeeiD, James T. LuiD, Nicole L. WashingtoniD

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Abstract

High quality population allele frequencies of DNA variants can be used to discover new biology, and study rare disorders. Here, we created a public catalog of mitochondrial DNA variants based on a population of 195,983 individuals. We focused on 3 criteria: (i) the population is not enriched for mitochondrial disorders, or other clinical phenotypes, (ii) all genomes are sequenced and analyzed in the same clinical laboratory, and (iii) both homoplasmic and heteroplasmic variants are reported. We found that 47% of the mitochondrial genome was invariant in this population, including large stretches in the 2 rRNA genes. This information could be used to annotate the mitochondrial genome in future studies. We also showed how to use this resource for the interpretation of pathogenic variants for rare mitochondrial disorders. For example, 42% of variants previously reported to be pathogenic for Leber Hereditary Optic Neuropathy (LHON) should be reclassified.

Abstract summary

Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract · CC BY-NC 4.0

Allele frequencies for homoplasmic and heteroplasmic mitochondrial variants across 195,983 sequenced genomes leave 47% of the mitochondrial genome invariant and put 42% of reported LHON variants in doubt.

Judging whether a mitochondrial variant causes disease needs frequencies from a population that is not itself enriched for mitochondrial disorders and that reports heteroplasmic as well as homoplasmic calls. This catalog is built to those criteria from genomes processed in one clinical laboratory, and is then used to argue that a large share of variants previously reported as pathogenic for Leber hereditary optic neuropathy (LHON) should be reclassified.

Key results

  1. ShownNearly half of the mitochondrial genome carries no variation in this population, with long invariant stretches in both ribosomal RNA genes.

    47% of the mitochondrial genome was invariant across the cohort, including large stretches in the 2 rRNA genes; the abstract does not give per-base coverage or the heteroplasmy threshold behind the call. · Abstract

  2. SuggestedApplying the population frequencies to a rare mitochondrial disease implies that a large share of catalogued LHON alleles should be reclassified.

    42% of variants previously reported as pathogenic for Leber hereditary optic neuropathy are said to warrant reclassification; the reclassification criteria, frequency cut-off and number of variants assessed are not stated. · Abstract

  3. ClaimedThe resource is a public mitochondrial allele-frequency catalog built to three stated design criteria.

    195,983 individuals, none selected for mitochondrial or other clinical phenotypes, all sequenced and analysed by the same clinical laboratory, with homoplasmic and heteroplasmic variants both reported. · Abstract

Methods, data and reproducibility

A population allele-frequency catalog of mitochondrial DNA variation, assembled from whole genomes sequenced and analysed in a single clinical laboratory on a cohort not selected for mitochondrial or other clinical phenotypes, retaining both homoplasmic and heteroplasmic calls; the frequencies are then applied to variants previously annotated as pathogenic.

  • sequenced genomes forming the mitochondrial variant catalog, from a population not enriched for mitochondrial disorders or other clinical phenotypes · human · n = 195,983 individuals
  • variants previously annotated as pathogenic for Leber hereditary optic neuropathy, reassessed against the catalog · human
Reproducibility gaps
The catalog is described as public, but the abstract gives no URL, browser or accession for it, and the sequencing and variant-calling pipeline is identified only as that of one clinical laboratory.
Limitations (2)
  • Frequencies come from one cohort processed by one laboratory pipeline; ancestry composition and sequencing depth, which both affect heteroplasmy detection, are not described. · noted in this summary
  • The LHON reclassification is reported only as a percentage, with no criteria, frequency threshold or count of variants reviewed. · noted in this summary

Read this if you interpret mitochondrial variants in rare disease and want population frequencies that include heteroplasmy when filtering candidate pathogenic mtDNA alleles.

Citations
58

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