Submissions for variant NC_012920.1:m.8851T>C

dbSNP: rs199476136

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002221472	SCV002498784	uncertain significance	Mitochondrial disease	2022-03-24	reviewed by expert panel	curation	The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one with onset in early 20s, one with onset in 50s). Several affected individuals had a period of normal development followed by delay and regression. Progressive neuromuscular involvement in later onset forms has also been seen. Features include developmental delay, microcephaly, choreoathetotic movements, ataxia, axonal neuropathy, progressive cognitive impairment, retinal dystrophy, hearing loss, and increase of subsarcolemmal mitochondria in muscle. Brain MRI showed bilateral basal ganglia lesions, Leigh syndrome, and cerebellar atrophy; and lab abnormalities included elevated blood and CSF lactate, and elevated ammonia with febrile viral infection. Heteroplasmy levels were generally variable, >68% in multiple tissues; one healthy mother had 85% heteroplasmy; and one healthy sib had 50-60% heteroplasmy (PS4_supporting; PMIDs: 8554662, 23206802, 33704825). There are no reports of de novo occurrence 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; PMIDs: 8554662, 23206802). There are several occurrences of this variant in healthy population databases. Several studies in yeast (PMID: 31181185) support the functional impact of this variant and showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.69 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000144005	SCV000997375	likely pathogenic	Leigh syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.8851T>C (YP_003024031.1:p.Trp109Arg) variant in MTATP6 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PM10, PP3, PP4, PP6
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268336	SCV001447187	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000144005	SCV001950073	likely pathogenic	Leigh syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This variant was identified as homoplasmic
Mendelics	RCV001542705	SCV002517646	uncertain significance	Leber optic atrophy	2023-04-21	criteria provided, single submitter	clinical testing
OMIM	RCV000010280	SCV000030504	pathogenic	Striatonigral degeneration, infantile, mitochondrial	2007-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000144005	SCV000188892	not provided	Leigh syndrome		no assertion provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542705	SCV001760536	pathogenic	Leber optic atrophy		no assertion criteria provided	clinical testing