Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000791268 | SCV005187324 | likely pathogenic | Mitochondrial disease | 2023-06-26 | reviewed by expert panel | curation | The m.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy. There was limited testing in family members precluding considering of segregation evidence. There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time. There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65). Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate). 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 consistent phenotypes in affected individuals and strong functional evidence showing impaired modification of the tRNA. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_moderate. |
| Centre for Mendelian Genomics, |
RCV000414832 | SCV000492835 | uncertain significance | Sudden cardiac death; Failure to thrive; Constipation; Jaundice; Generalized hypotonia; Infantile onset; Neonatal onset | 2015-09-21 | criteria provided, single submitter | clinical testing | |
| Undiagnosed Diseases Network, |
RCV000791268 | SCV000930554 | pathogenic | Mitochondrial disease | 2019-03-13 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000032775 | SCV000056539 | uncertain significance | Variant of unknown significance | 1992-08-01 | no assertion criteria provided | literature only |