ClinVar Miner

Submissions for variant NC_012920.1(MT-ATP6):m.9176T>C

dbSNP: rs199476135
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV002260585 SCV002540733 pathogenic Mitochondrial disease 2022-06-30 reviewed by expert panel curation 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000010279 SCV000997504 pathogenic Leigh syndrome 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.9176T>C (YP_003024031.1:p.Leu217Pro) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP3, PP4
Mendelics RCV001542707 SCV002517651 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV002251425 SCV002522139 pathogenic Maternally-inherited spastic paraplegia 2022-06-01 criteria provided, single submitter clinical testing homoplasmic, Seq.depth: 1730x
Pediatric Department, Xiangya Hospital, Central South University RCV000010279 SCV002761210 pathogenic Leigh syndrome criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf RCV000010279 SCV004171139 pathogenic Leigh syndrome criteria provided, single submitter not provided
Institute of Human Genetics, University of Leipzig Medical Center RCV002251425 SCV004175998 pathogenic Maternally-inherited spastic paraplegia 2023-11-23 criteria provided, single submitter clinical testing Criteria applied: PS4,PM5,PP1_MOD,PS3_SUP,PM2_SUP,PP3
Institute of Human Genetics, University of Leipzig Medical Center RCV000010279 SCV004812111 pathogenic Leigh syndrome 2024-03-28 criteria provided, single submitter clinical testing Criteria applied: PS4,PM5,PP1_MOD,PS3_SUP,PM2_SUP
OMIM RCV000010278 SCV000030502 pathogenic Striatonigral degeneration, infantile, mitochondrial 1998-05-01 no assertion criteria provided literature only
GeneReviews RCV000010279 SCV000188895 not provided Leigh syndrome no assertion provided literature only
OMIM RCV000754652 SCV000882575 pathogenic Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 1998-05-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV001027501 SCV001190076 uncertain significance not provided no assertion criteria provided provider interpretation
Genomics England Pilot Project, Genomics England RCV001542707 SCV001760538 likely pathogenic Leber optic atrophy no assertion criteria provided clinical testing
OMIM RCV004554599 SCV005044509 pathogenic LEIGH SYNDROME, MITOCHONDRIAL 1998-05-01 no assertion criteria provided literature only

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