rs207460002
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_SupportingPP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120621/MONDO:0044970/014
Frequency
Consequence
ENST00000361789.2 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
- mitochondrial complex III deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Leber hereditary optic neuropathyInheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000361789.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MT-CYB | ENST00000361789.2 | TSL:6 | c.833A>G | p.Tyr278Cys | missense | Exon 1 of 1 | ENSP00000354554.2 |
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1
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
Leber optic atrophy Pathogenic:1
Multisystem disorder Pathogenic:1
Mitochondrial disease Uncertain:1
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.
Computational scores
Source: