Mitochondrial Diseases VCEP
The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1992 (Leber Hereditary Optic Neuropathy or LHON, PMID: 1322638; hearing loss, PMID: 16500624), however other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at high frequencies in population databases. Furthermore, this variant has been seen in individuals with other well-known pathogenic mitochondrial DNA variants (family with LHON and m.3460G>A, PMID: 7901141; family with hearing loss and m.1555A>G, PMID: 16152638; BP2). The variant was seen at homoplasmy in affected and unaffected family members in several of these publications precluding consideration of segregation evidence. There are no reported de novo occurrences of this variant to our knowledge. Some functional characterization was performed in patient cells, however abnormalities noted were nonspecific and other genetic etiologies were not assessed (PMID: 1322638). This variant is present at considerable frequencies in population databases (BS1). The frequency in the MITOMAP GenBank sequences is 206/59,389 (0.347%; 12/12 individuals in Hg V7, 3/3 individuals in Hg H40b, 4/4 individuals in V7b, 4/4 individuals in W4b, 84/86 individuals in V7a, also seen in individuals from M22b, M38a, H11, HV20, P2, B2e, and others). The frequency in gnomAD v3.1.2 is 302/56,419 (0.535%). Indeed, there are 302 homoplasmic occurrences (seen in all populations except Amish and Middle Eastern, seen across every haplogroup listed; seen in individuals ages 30 years to >80 years) in addition to 10 heteroplasmic occurrences (seen in multiple populations, haplogroups, and heteroplasmy levels). The frequency in the Helix dataset is 775/195,983 (0.395%). Indeed, there are 775 homoplasmic occurrences (seen across many haplogroups) and 24 heteroplasmic occurrences (seen across many haplogroups). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP2.
