Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NC_012920.1:m.9176T>C

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

Met criteria codes 5
PS3_Supporting PP1_Moderate PP3 PM5 PS4
Not Met criteria codes 8
PVS1 BA1 BP4 BS1 PM6 PM2 PS2 PS1

Evidence Links 2

Expert Panel

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.
Met criteria codes
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
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).
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).
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)
Not Met criteria codes
PVS1
Single nt change
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.
BP4
APOGEE score 0.92 (P)
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.
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.
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.
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