ClinVar Miner

Submissions for variant NC_012920.1(MT-ND6):m.14487T>C

dbSNP: rs199476109
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Total submissions: 6
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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 RCV003162239 SCV003915437 pathogenic Mitochondrial disease 2022-08-08 reviewed by expert panel curation The m.14487T>C (p.M63V) variant in MT-ND6 has been reported in at least 37 unrelated individuals with primary mitochondrial disease (PS4; PMIDs: 30741831, 33706792, 34223155, 32162843, 30461153, 30128709, 30095618, 28122886, 28429146, 27338358, 26530508, 23813926, 23463613, 24126373, 23847141, 23010433, 21364701, 21196529, 19062322, 18977334, 17535832, 16044424, 15625630, 15576045, 14595656, 14520668, 14684687, 20019223). Features seen in affected individuals include Leigh syndrome spectrum and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as ataxia, dystonia, epilepsy, optic neuropathy, and ptosis. Heteroplasmy levels were variable in affected individuals as was age of onset (infancy to adulthood). 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; PMIDs: 14684687,17535832, 20019223, 24126373, 26530508, 28122886). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656). 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/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000144020 SCV000998164 pathogenic Leigh syndrome 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.14487T>C (YP_003024037.1:p.Met63Val) variant in MTND6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3
Mendelics RCV002247307 SCV002517681 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000010333 SCV000030559 pathogenic Leigh syndrome due to mitochondrial complex I deficiency 2003-11-01 no assertion criteria provided literature only
OMIM RCV000010334 SCV000030560 pathogenic Striatal necrosis, bilateral, with dystonia 2003-11-01 no assertion criteria provided literature only
GeneReviews RCV000144020 SCV000188912 not provided Leigh syndrome no assertion provided literature only

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