ClinVar Miner

Submissions for variant NC_012920.1(MT-ND5):m.13051G>A

dbSNP: rs1131692063
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Total submissions: 4
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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 RCV000495629 SCV005088549 uncertain significance Mitochondrial disease 2023-05-23 reviewed by expert panel curation The m.13051G>A (p.G239S) variant in MT-ND5 has been reported in thirteen individuals with primary mitochondrial disease from four kindreds (PS4_moderate; PMIDs: 12736867, 27164671). Age of onset varied from age 18 months to the 40s, and clinical features were consistent with Leber Hereditary Optic Neuropathy (LHON) and Leigh syndrome spectrum disorders, in addition to hearing loss, optic atrophy, retinal dystrophy, ophthalmoplegia, and seizures. Several individuals had elevated lactate levels. The variant was present at or near homoplasmy in all reported individuals, thus precluding consideration for segregation evidence. There are no reports of confirmed de novo occurrences to our knowledge. This variant is absent in the GenBank dataset and gnomAD v3.1.2, however there were three heteroplasmic occurrences in the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.71 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Comprehensive analysis in patient cells showed increased reactive oxygen species and increased mitophagy (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner, although this Expert Panel notes this is a very compelling variant of uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000854887 SCV000997932 likely pathogenic Leber optic atrophy 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.13051G>A (YP_003024036.1:p.Gly239Ser) variant in MTND5 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, PP4,PP7
Mendelics RCV000854887 SCV002517676 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
Wellcome Centre for Mitochondrial Research, Newcastle University RCV000495629 SCV000577891 pathogenic Mitochondrial disease 2017-05-22 no assertion criteria provided clinical testing

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