Variant: NC_012920.1:m.9155A>G

CA414802316

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: c1ae9220-4e74-423b-ae48-f73d8ece2832

HGVS expressions

NC_012920.1:m.9155A>G
J01415.2:m.9155A>G
ENST00000361899.2:n.629A>G

Likely Pathogenic

• Met criteria codes: PP3 PM6 PM2_Supporting PS4_Moderate

• Not Met criteria codes: PS3 PS2 PP1

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.9155A>G (p.Q210R) variant in MT-ATP6 has been reported in three unrelated individuals in the literature (PMIDs: 34961688, 27966441, 27450679) and has been reported to have been seen by experts on this panel in an additional three unrelated individuals. Heteroplasmy levels were variable in affected individuals as were mitochondrial disease features, although diabetes and deafness were reported in several individuals (PS4_moderate; PMIDs: 34961688, 27966441, 27450679). The variant occurred in de novo in one of the cases reported by an expert on this panel and in one of the cases reported in the literature (PS2_moderate; PMID: 27450679). There are no large families reported in the medical literature to consider for evidence of 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 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids or single fiber studies reported on this variant. 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS2_moderate, PS4_moderate, PM2_supporting, PP3.

Met criteria codes

• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
• PM6: The variant occurred in de novo in one of the cases reported by an expert on this panel and in one of the cases reported in the literature (proband had 88% heteroplasmy in muscle; variant was undetectable in mother's blood and muscle; PS2_moderate; PMID: 27450679).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (Mitomap: 0/54594, gnomAD: 0/56434, Helix: 0/195983; PM2_supporting).
• PS4_Moderate: The m.9155A>G (p.Q210R) variant in MT-ATP6 has been reported in three unrelated individuals in the literature (PMIDs: 34961688, 27966441, 27450679) and has been reported to have been seen by experts on this panel in an additional three unrelated individuals. Heteroplasmy levels were variable in affected individuals as were mitochondrial disease features, although diabetes and deafness were reported in several individuals (PS4_moderate; PMIDs: 34961688, 27966441, 27450679).

Not Met criteria codes

• PS3: There are no cybrids or single fiber studies reported on this variant.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: There are no large families reported in the medical literature to consider for evidence of segregation.

Approved on: 2022-07-25

Published on: 2022-10-12