Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NC_012920.1:m.9176T>C

Curation Version - 1.0
Curation History
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CA120597

9644 (ClinVar)

Gene: MT-ATP6

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

Link to MONDO

UUID: 7d8bbc0a-2bbd-48ce-8853-5d3dc1dffbf0

Approved on: 2022-06-30

Published on: 2022-06-30

HGVS expressions

NC_012920.1:m.9176T>C

J01415.2:m.9176T>C

ENST00000361899.2:n.650T>C

Pathogenic

PP1_Moderate PS3_Supporting PS4 PP3 PM5

PS2 PS1 BP4 BA1 PVS1 PM6 PM2 BS1

Evidence Links 2

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.9176T>C (p.L217P) variant in MT-ATP6 has been reported in more than 16 unrelated individuals with features of primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to 20s). Features included Leigh syndrome (including several cases with adult-onset Leigh syndrome) and NARP, as well as seizures, ataxia, muscle weakness, dystonia, axonal neuropathy, migraines, sensorineural hearing loss, hypertrophic cardiomyopathy, ophthalmoplegia, ptosis, and pigmentary retinopathy. Heteroplasmy levels were generally >90% in affected individuals (PS4; PMIDs: 17209980, 15709156, 11198506, 27408822, 30136164, 20656066, 21819970, 19747204, 9631394, 9501263, 9270604, 7668837). There are no reports of de novo occurrences of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 21819970, 9270604, 7668837). This variant is present in three sequences from GenBank dataset, however 2/3 sequences are from individuals with primary mitochondrial disease. This variant is not present in the homoplasmic state in any individuals in the gnomAD v3.1.2 dataset, however two individuals have this variant in the 50-60% heteroplasmy range and one in the 80-90% heteroplasmy range. There is one homoplasmic occurrence in the Helix dataset. This variant is located at the same amino acid position as another well-known pathogenic variant, m.9176T>G (p.L217R) (PM5). While cybrid studies were performed (PMID: 19160410), there was insufficient evidence reported to meet criteria for cybrid scoring per the specified guidelines for variant curation. Studies in yeast (PMID: 20056103) support the functional impact of this variant (PS3_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.92 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as 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 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PP1_moderate, PM5, PP3.

PP1_Moderate

This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 21819970, 9270604, 7668837).

PS3_Supporting

While cybrid studies were performed (PMID: 19160410), there was insufficient evidence reported to meet criteria for cybrid scoring per the specified guidelines for variant curation. Studies in yeast (PMID: 20056103) support the functional impact of this variant (PS3_supporting).

Growth: The atp6-L247P mutant grew nearly identically to the wild type on a non-fermentable substrate (glycerol). Respiration rate – assessed oxygen consumption with NADH as electron donor and in the presence of uncoupler (CCCP), oxygen consumption increased in WT and mutant but more in WT; measures in presence of substrates that donate electron to complex IV, activity reduced 35% in mutant compared to WT ATPase activity 30% ATP reduction deficit is concerning for pathogenicity; measured rate of ATP synthesis with NADH as a respiratory substrate and activity was reduced in mutant by ∼30% compared with the WT ATPase assembly mutant and WT distinguished with antibodies against Atp9p and subunit α (Atp1p), which detected evidence of an Atp9p-ring, free F1, and incomplete α subunit assemblies in the mutant sample only PubMed:20056103

Not sufficient evidence to meet criteria for scoring cybrid: Biochemical deficiency observed in primary patient cell line (patient 2 in Dionisi-Vici et al, PMID: 9501263): Oligomycin-sensitve ATPase activity as well as the global ATP production in cultured fibroblasts were normal; variant was nearly homoplasmic in patient fibroblasts Transfer of deficiency to cybrids: growth (similar behavior when grown in galactose compared to controls - figure 1E); ATP synthesis (60% of controls observed, not correlated to mutant load because only homoplasmic mutant clones generated for this variant); ATPase activity (OS-ATPase activity similar to controls; variant did not affect sensitivity to oligomycin during sonication which was similar to controls); polarographic studies were more limited because could not compare to own controls (0% mutant) however activities seen were similar to Rho+ cells and other clone (L156P) which which did not affect rate of state 3, respiratory control index and ATP synthase activity calculated from state 3 Cybrid heteroplasmy level: only 100% mutant clones could be obtained Reproduced and consistent: yes PubMed:19160410

PS4

This variant has been reported in more than 16 unrelated individuals with features of primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to 20s). Features included Leigh syndrome (including several cases with adult-onset Leigh syndrome) and NARP, as well as seizures, ataxia, muscle weakness, dystonia, axonal neuropathy, migraines, sensorineural hearing loss, hypertrophic cardiomyopathy, ophthalmoplegia, ptosis, and pigmentary retinopathy. Heteroplasmy levels were generally >90% in affected individuals (PS4; PMIDs: 17209980, 15709156, 11198506, 27408822, 30136164, 20656066, 21819970, 19747204, 9631394, 9501263, 9270604, 7668837)

PP3

The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.92 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

PM5

This variant is located at the same amino acid position as another well-known pathogenic variant, m.9176T>G (p.L217R) (PM5).

PS2

There are no reports of de novo occurrence of this variant. No reports of de novo inheritance (per Ganetzky et al., 2019 and curator review as of 1/27/2021).

PS1

No other nucleotide changes resulting in same aa change reported.

BP4

APOGEE score 0.92 (P)

BA1

Present in 3 sequences in Genbank dataset for a frequency of 0.006% (queried 1/28/21) - 1 occurrence each in J2a, J1c, and U5b.

PVS1

Single nt change

PM6

There are no reports of de novo occurrence of this variant. No reports of de novo inheritance (per Ganetzky et al., 2019 and curator review as of 1/27/2021).

PM2

This variant is present in three sequences from GenBank dataset, however 2/3 sequences are from individuals with primary mitochondrial disease. This variant is not present in the homoplasmic state in any individuals in the gnomAD v3.1.2 dataset, however two individuals have this variant in the 50-60% heteroplasmy range and one in the 80-90% heteroplasmy range. There is one homoplasmic occurrence in the Helix dataset.

BS1

Present in 3 sequences in Genbank dataset for a frequency of 0.006% (queried 1/28/21) - 1 occurrence each in J2a, J1c, and U5b.

Curation History

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