The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR

  • See Evidence submitted by expert panel for details.

Variant: NC_012920.1:m.9191T>C

CA345914

40153 (ClinVar)

Gene: MT-ATP6
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
UUID: 34880844-b4da-4064-a8c0-6a3e6a05ad7c
Approved on: 2022-03-24
Published on: 2022-03-24

HGVS expressions

NC_012920.1:m.9191T>C
J01415.2:m.9191T>C
ENST00000361899.2:n.665T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM2_Supporting PS3_Supporting PM6_Supporting PP3
Not Met criteria codes 4
PM5 PVS1 PS1 PS4

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.9191T>C (p.L222P) variant in MT-ATP6 has been reported once in the literature (PMID: 16217706, patient 2) in an individual with Leigh syndrome (94% heteroplasmy in muscle and 90% in fibroblasts; only testing done was MT-ATP6 and MT-ATP8 sequencing). This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant occurred de novo in this individual (absent in blood from mother and sister; PM6_supporting, PMID: 16217706). There are no large families reported in the 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 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Yeast model showed (1) failure to grow on glycerol (indicating at least an 80% reduction in ATP synthase activity/function), (2) 67-85% decrease in oxygen consumption, (3) <10% of control ATP synthesis, and (4) impaired ATPase assembly (PS3_supporting, PMID: 24316278). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given consistent functional evidence of severe deleterious effect and rare nature of the variant, as well as being absent in healthy cohorts even at low heteroplasmy levels. In summary, this variant is 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 January 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM6_supporting, PP3.
Met criteria codes
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Queried genbank, helix, gnomad 1/5/2022
PS3_Supporting
Yeast model showed (1) failure to grow on glycerol (indicating at least an 80% reduction in ATP synthase activity/function), (2) 67-85% decrease in oxygen consumption, (3) <10% of control ATP synthesis, and (4) impaired ATPase assembly (PS3_supporting, PMID: 24316278).

PM6_Supporting
This variant has been identified as a de novo occurrence in one individual with features consistent with primary mitochondrial disease (PM6_supporting, PMID: 16217706; per ClinGen de novo scoring guidance, scored 0.5 points for being absent in blood from mother and sister).
PP3
In silico tools (APOGEE) predict this variant to be pathogenic with a score of 0.75 (PP3).
Not Met criteria codes
PM5
No other amino acid changes at this position have been reported.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No other nucleotide changes resulting in this amino acid change have been reported.
PS4
This variant has been reported only once in the literature (PMID: 16217706, patient 2) in an individual with Leigh syndrome (94% heteroplasmy in muscle and 90% in fibroblasts; only testing done was MT-ATP6 and MT-ATP8 sequencing). This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals.
Curation History
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