ClinVar Miner

Submissions for variant NC_012920.1:m.8993T>C (rs199476133)

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Total submissions: 7
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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 RCV000495030 SCV001736752 pathogenic Mitochondrial diseases 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variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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
OMIM RCV000754647 SCV000030499 pathogenic Mitochondrial complex v (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 pathogenic Leigh syndrome 2014-04-17 no assertion criteria provided literature only
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000495030 SCV000577898 pathogenic Mitochondrial diseases 2017-05-22 no assertion criteria provided clinical testing

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