Mitochondrial Diseases VCEP
The m.7445A>G variant is located in the MT-TS1 precursor, overlapping with MT-CO1 (Term514Term). This variant has been reported in at least 32 individuals with primary mitochondrial disease, and the only consistent reported feature in affected individuals was hearing loss (PS4; PMIDs: 8019558, 8572257, 9450881, 11069477, 11175301, 15620132, 16092542, 15987292, 23525847, 18537605, 22567359, 21621438, 30035268, 26328603, 29605341, 32169613). Some individuals with this variant have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. The age of onset ranges from infancy to adulthood. The variant is primarily seen in the homoplasmic state however some individuals were reported to have low heteroplasmy levels in blood. Several extended families have been reported in the medical literature however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for segregation evidence of pathogenicity. There are no reports of de novo occurrences in the medical literature to our knowledge however the presence of this variant in individuals from different haplogroups suggests this variant occurred de novo in the ancestors of these individuals of different backgrounds. Of note, another 137 elderly individuals were found to carry this variant in platelets with heteroplasmy levels >2%, and this was reported to significantly correlate with high frequency hearing loss (PMID: 26328603), however these cases were excluded from this curation given the lack of other clinical details. There is one occurrence of this variant in the Mitomap GenBank dataset, however this is from an individual with known mitochondrial disease. This variant is absent in gnomAD v3.1.2. There are six heteroplasmic occurrences in the Helix dataset. Although there are several occurrences, the frequency is still low (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Cybrid studies supported the functional impact of this variant (PS3_supporting). One study showed a 60-70% reduction of steady state ND6 levels and 40-50% reduction of tRNASer (PMID: 15694374). Other cell line studies showed significantly reduced Complex I activity, with lesser reduction in Complex IV (P=0.05; PMID 29934116). Of note, there is one early cell line study that did not demonstrate any bioenergetic impact of this variant (PMID: 9247714). In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the extent of cases with similar phenotypes from different ethnic backgrounds that have been reported, that is further supported by the evidence outlined above. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PM2_supporting, PS3_supporting.
