Variant: NC_012920.1(MT-ATP8):m.8430T>C

CA414796067

692855 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 094e95af-4931-4039-8ed1-df7cad756a56

Approved on: 2025-01-13

Published on: 2025-05-21

HGVS expressions

NC_012920.1:m.8430T>C
J01415.2:m.8430T>C
ENST00000361851.1:c.65T>C

Uncertain Significance

• Met criteria codes: PP1_Moderate PM2_Supporting PS4_Supporting

• Not Met criteria codes: PS3 PP3 BP4

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.8430T>C (p.L22P) variant in MT-ATP8 has not been reported in the medical literature however three unrelated families with features consistent with primary mitochondrial disease are known to members of this Expert Panel (PS4_supporting). Clinical features in affected individuals include Leigh syndrome spectrum disorder, neuropathy, mood disorder, cardiomyopathy, retinal dystrophy, and hearing loss. Heteroplasmy levels ranged from 57% to homoplasmic in blood. The variant segregated with disease manifestations in one family (PP1_moderate). This variant is present in population databases at low frequency (0.002%; one homoplasmic occurrence in MITOMAP; one homoplasmic and one heteroplasmic occurrence in gnomAD v3.1.2; three homoplasmic and three heteroplasmic occurrences in the Helix database; PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.51 however the updated APOGEE2 predicts an unknown effect on protein with a score of 0.366 (Min=0, Max=1). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 January 13, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting.

Met criteria codes

• PP1_Moderate: The variant segregated with disease manifestations in one family (PP1_moderate).
• PM2_Supporting: This variant is present in population databases at low frequency (0.002%; one homoplasmic occurrence in MITOMAP; one homoplasmic and one heteroplasmic occurrence in gnomAD v3.1.2; three homoplasmic and three heteroplasmic occurrences in the Helix database; PM2_supporting).
• PS4_Supporting: The m.8430T>C (p.L22P) variant in MT-ATP8 has not been reported in the medical literature however three unrelated families with features of primary mitochondrial disease are known to members of this Expert Panel (PS4_supporting). Clinical features in affected individuals include Leigh syndrome spectrum disorder, neuropathy, mood disorder, cardiomyopathy, retinal dystrophy, and hearing loss. Heteroplasmy levels ranged from 57% to homoplasmic in blood.

Not Met criteria codes

• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PP3: The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.51 however the updated APOGEE2 predicts an unknown effect on protein with a score of 0.366 (Min=0, Max=1).
• BP4: The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.51 however the updated APOGEE2 predicts an unknown effect on protein with a score of 0.366 (Min=0, Max=1).