Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV002260588 | SCV002540723 | likely pathogenic | Mitochondrial disease | 2022-06-30 | reviewed by expert panel | curation | The m.14495A>G (p.L60S) variant in MT-ND6 has been reported in five individuals from three families, all of whom had LHON (PS4_supporting; PMIDs: 2287992, 11133798). There are no reports of de novo occurrences to our knowledge. This variant segregated with disease in one family with LHON (all testing was performed in blood; affected individuals: proband/mother with variant present at 51% heteroplasmy, sons with variant at 93% and 92%; unaffected individuals: sister with variant at 23%, maternal niece with variant at 53%, and maternal nephew with variant at 37%; PP1_moderate; PMID: 11133798). 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 0.87 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the strong segregation evidence and consistent phenotype in affected individuals. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3. |
OMIM | RCV000010330 | SCV000030556 | pathogenic | Leber optic atrophy | 2001-01-01 | no assertion criteria provided | literature only | |
Gene |
RCV000010330 | SCV000086626 | 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. |