Submissions for variant NC_012920.1(MT-ATP6):m.8993T>C

dbSNP: rs199476133

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000495030	SCV001736752	pathogenic	Mitochondrial disease	2021-02-17	reviewed by expert panel	curation	The m.8993T>C (p.L156P) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and who had features variably consistent with Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (PS4; PMIDs: 8395787, 16532470, 30128709, 29101127, 28003964, 26265210, 22819295, 19046652, 18055910, 16049925, 10604142). Per our literature review and a recently published review, there are no published de novo occurrences of this variant (PMID: 30763462). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>G (p.L156R) (PM5). 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; PMID: 10604142). In silico tools predict this variant to be pathogenic (PP3). Cybrid studies (homoplasmic for this variant) showed reduced ATP production compared to Rho+ control cell lines (PS3_supporting; PMID: 19160410). 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 February 17, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5, PP1_moderate, PP3).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000854390	SCV000997425	pathogenic	NARP syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.8993T>C (YP_003024031.1:p.Leu156Pro) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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, PS3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268873	SCV001448091	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mendelics	RCV002247300	SCV002517648	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000010275	SCV002761213	pathogenic	Leigh syndrome		criteria provided, single submitter	clinical testing
OMIM	RCV000754647	SCV000030499	pathogenic	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1	2007-12-01	no assertion criteria provided	literature only
OMIM	RCV000010276	SCV000030500	pathogenic	Ataxia and polyneuropathy, adult-onset	2007-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000010275	SCV000188894	not provided	Leigh syndrome		no assertion provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000495030	SCV000577898	pathogenic	Mitochondrial disease	2017-05-22	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV000854390	SCV004812018	pathogenic	NARP syndrome	2024-02-22	no assertion criteria provided	clinical testing