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

dbSNP: rs199476135

Total submissions: 15

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
Solve-RD Consortium	RCV004766998	SCV005199973	likely pathogenic	NARP syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team