Submissions for variant NC_012920.1(MT-ATP6):m.9185T>C

dbSNP: rs199476138

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000495689	SCV002540722	pathogenic	Mitochondrial disease	2022-06-30	reviewed by expert panel	curation	The m.9185T>C (p.L220P) variant in MT-ATP6 has been reported in more than 16 individuals with features of primary mitochondrial disease with manifestations including Leigh syndrome, MELAS, NARP, neuropathy, ataxia, exercise intolerance, muscle weakness, developmental delay, and seizures (PS4; PMIDs: 28429146, 33717984, 27290639, 24153443, 27783406, 32042921, 31500933, 29116603, 31187502, 22577227, 25548692, 18461509, 17352390, 29228836, 16217706). There are at least two reports of de novo occurrences of this variant (PM6; PMIDs: 33717984, 29228836). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 16217706, 17352390,20546952). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (three occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). Studies in cybrids support the functional impact of this variant (PS3_supporting; PMID: 24153443). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.94 (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 U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PS3_supporting, PP1_moderate, PM2_supporting, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000010282	SCV000997508	pathogenic	Leigh syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.9185T>C (YP_003024031.1:p.Leu220Pro) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001267926	SCV001367861	uncertain significance	not provided	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3. This variant was detected in mitochondrial heteroplasmy state.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267926	SCV001446438	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mendelics	RCV001542709	SCV002517652	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002267606	SCV002549861	pathogenic	Mitochondrial DNA-Associated Leigh Syndrome and NARP	2022-07-11	criteria provided, single submitter	clinical testing	_x000D_This variant was identified as homoplasmic. Criteria applied: PS2, PS4, PP1_MOD, PP3, PM2_SUP
MGZ Medical Genetics Center	RCV000754648	SCV002580116	pathogenic	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1	2022-06-14	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV003224857	SCV003920923	pathogenic	Charcot-Marie-Tooth disease, type IA	2022-09-12	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001267926	SCV005199236	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760325	SCV005368439	pathogenic	NARP syndrome	2024-09-24	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM6,PP1_MOD,PS3_SUP,PM2_SUP,PP3
OMIM	RCV000754648	SCV000030506	pathogenic	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1	2007-04-15	no assertion criteria provided	literature only
GeneReviews	RCV000010282	SCV000188897	not provided	Leigh syndrome		no assertion provided	literature only
GeneReviews	RCV000240612	SCV000299229	pathogenic	Charcot-Marie-Tooth disease	2016-09-01	no assertion criteria provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000495689	SCV000577900	pathogenic	Mitochondrial disease	2017-05-22	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542709	SCV001760540	likely pathogenic	Leber optic atrophy		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV004760325	SCV005199974	likely pathogenic	NARP syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team