Variant: NC_012920.1(MT-ATP6):m.9035T>C

CA414801955

690280 (ClinVar)

Gene: MT-ATP6

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 4406e032-85d0-428e-bba3-649609672a37

HGVS expressions

NC_012920.1:m.9035T>C
J01415.2:m.9035T>C
ENST00000361899.2:n.509T>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS3_Moderate PS4_Moderate PP3

• Not Met criteria codes: PS2 PP1 PM6

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.9035T>C (p.L170P) variant in MT-ATP6 has been reported in 10 unrelated individuals with primary mitochondrial disease with shared features of cerebellar ataxia, progressive gait disturbance, sensory neuropathy, and fatigue; several showed developmental delays and learning disabilities (PS4_moderate; five from the literature; PMIDs: 19626676; 22577227; 31187502; an additional five cases with the same clinical presentations as above were submitted to this VCEP from expert panel members, and the expert panel agreed to include these cases). All cases were homoplasmic or near-homoplasmic (94-98%). There are no reported de novo occurrences of this variant to our knowledge. The first case reported with this variant (PMID: 19626676) was a member of a 4-generation, 17-member family with 16 affected maternal family members – the only one unaffected was the son of an affected male. Given this variant typically occurs at homoplasmy, there are no large families with varying heteroplasmy levels to consider for segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies show two different classes of function defects: (1) 85% reduction of F1F0 ATP synthase activity and a resulting 40-50% reduction in ATP output, and (2) an 8-fold higher level of damaging ROS (PS3_moderate; PMID: 19626676). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3, PM2_supporting, PS3_moderate.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). [AF is is 0.0000% in Mitomap (0/54594), gnomAD (0/56434), and Helix (0/195983)]
• PS3_Moderate: Cybrid studies show two different classes of function defects: (1) 85% reduction of F1F0 ATP synthase activity and a resulting 40-50% reduction in ATP output, and (2) an 8-fold higher level of damaging ROS (PS3_moderate; PMID: 19626676). [Cybrids showed two different functional impacts. They had (1) "reduced oligomycin-sensitive ATP hydrolyzing activity with less than half of the steady-state content of ATP", and (2) nearly an 8-fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary-butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ(10) and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease."]
• PS4_Moderate: The m.9035T>C (p.L170P) variant in MT-ATP6 has been reported in 10 unrelated individuals with primary mitochondrial disease with shared features of cerebellar ataxia, progressive gait disturbance, sensory neuropathy, and fatigue; several showed developmental delays and learning disabilities (PS4_moderate; five from the literature; PMIDs: 19626676; 22577227; 31187502; an additional five cases with the same clinical presentations as above were submitted to this VCEP from expert panel members, and the expert panel agreed to include these cases). All cases were homoplasmic or near-homoplasmic (94-98%).
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

Not Met criteria codes

• PS2: There are no reported de novo occurrences of this variant to our knowledge.
• PP1: The first case reported with this variant (PMID: 19626676) was a member of a 4-generation, 17-member family with 16 affected maternal family members – the only one unaffected was the son of an affected male. Given this variant typically occurs at homoplasmy, there are no large families with varying heteroplasmy levels to consider for segregation.
• PM6: There are no reported de novo occurrences of this variant to our knowledge.

Approved on: 2022-06-30

Published on: 2022-06-30