ClinVar Miner

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

dbSNP: rs199476136
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Total submissions: 8
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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 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 pathogenic Leber optic atrophy 2022-05-04 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 pathogenic Leigh syndrome 2021-12-02 no assertion criteria provided literature only
Genomics England Pilot Project,Genomics England RCV001542705 SCV001760536 pathogenic Leber optic atrophy no assertion criteria provided clinical testing

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