Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003153301 | SCV003842282 | uncertain significance | Mitochondrial disease | 2022-07-11 | reviewed by expert panel | curation | The m.15579A>G (p.Y278C) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This woman had exercise intolerance, epilepsy, intellectual disability, hearing loss, retinal dystrophy, and cataracts (PMID: 11601507). The variant was heteroplasmic in muscle (88%) and leucocytes (15%). The variant was reported as de novo as it was absent in mother’s blood, however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. 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 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). A dramatic reduction of Complex III activity and Complex III-driven ATP synthesis, enhanced superoxide production, and a perturbation of glutathione homeostasis were seen in a cybrid homoplasmic for this variant (PMID: 23418307; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic or pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214); PM2_supporting, PP3, PS3_supporting. |
| Wong Mito Lab, |
RCV000855325 | SCV000998375 | likely pathogenic | Mitochondrial myopathy with reversible cytochrome C oxidase deficiency | 2019-10-17 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.15579A>G (YP_003024038.1:p.Tyr278Cys) variant in MTCYB gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM8, PM9, PM10, PP4, PP6 |
| Mendelics | RCV002247306 | SCV002517661 | pathogenic | Leber optic atrophy | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000010321 | SCV000030546 | pathogenic | Multisystem disorder | 2001-10-01 | no assertion criteria provided | literature only |