ClinVar Miner

Submissions for variant m.4171C>A

dbSNP: rs28616230
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Total submissions: 5
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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 RCV002260596 SCV002540725 uncertain significance Mitochondrial disease 2022-06-30 reviewed by expert panel curation The m.4171C>A (p.L289M) variant in MT-ND1 has been reported in 13 individuals with primary mitochondrial disease with features falling under the LHON and/or Leigh syndrome spectrums with variable brain lesions (PS4_moderate, PMIDs: 12112111, 19555656, 20491810, 22879922, 24884847, 32652755, 34670133, 35104579, 32045392; Cui et al., 2006 with no PMID; of note, the two families in PMID: 12112111 might be in the same haplogroup although there is no known kinship). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are no reports of de novo occurrences to our knowledge. Although typically homoplasmic in kindreds, the variant has been reported to segregate with features of primary mitochondrial disease in two family members from one family (PMID: 12112111) however this did not meet criteria to be considered for PP1. This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (two occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.60 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). An E. coli model (homoplasmic for this variant) showed only a 13% decrease in enzyme activity, which did not reach statistical significance and therefore did not meet criteria to be considered for PS3 (PMID: 19616643). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. In the future, once three or more unrelated cases are reported, criteria for a likely pathogenic classification would be met. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022 (PMID: 32906214): Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000010384 SCV000996776 likely pathogenic Leber optic atrophy 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.4171C>A (YP_003024026.1:p.Leu289Met) variant in MTND1 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PP4
Mendelics RCV000010384 SCV002517669 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000010384 SCV000030610 pathogenic Leber optic atrophy 2002-05-01 no assertion criteria provided literature only
GeneReviews RCV000010384 SCV000086638 not provided Leber optic atrophy no assertion provided literature only This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.

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