Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV002260617 | SCV002540744 | likely pathogenic | Mitochondrial disease | 2022-06-30 | reviewed by expert panel | curation | The m.3890G>A (p.R195Q) variant in MT-ND1 has been reported in at least nine individuals from nine families in the literature, who had features falling within the Leber Hereditary Optic Neuropathy (LHON) or Leigh syndrome spectrums (PS4_moderate; PMIDs: 34390870, 33337510, 27798429, 18504678, 30095618, 23246842, 23847141). There are no reports of de novo occurrence of this variant to our knowledge. Although this variant most often is seen in the homoplasmic state, in one multi-generational family, there were five unaffected relatives with low heteroplasmy levels in urine and blood, compared to much higher levels in the proband (PP1_moderate; PMID 2324842). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease – PMID: 23246842; variant 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 0.73 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID: 23246842). In summary, this variant meets criteria to be classified as likely pathogenic 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 March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS4_moderate, PP3, PM2_supporting, PS3_supporting. |
Institute for Medical Genetics and Human Genetics, |
RCV002285011 | SCV002574883 | pathogenic | not specified | 2022-09-22 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000144000 | SCV000188886 | not provided | Leigh syndrome | no assertion provided | literature only |