Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002247294 | SCV003915444 | likely pathogenic | Mitochondrial disease | 2023-01-09 | reviewed by expert panel | curation | The m.12147G>A variant in MT-TH has been reported in two unrelated probands with features of primary mitochondrial disease. Both individuals were males with symptom onset in late teens to early 20s, developed seizures, and had COX-negative fibers identified on muscle biopsy. One individual also had ragged red fibers, and complex I and IV deficiencies. Additional features seen include sensorineural hearing loss, optic atrophy, ptosis, migraines, ataxia, myoclonus, muscle weakness, hepatic failure consistent with Reye syndrome, lactic acidosis, and hyperCKemia. Heteroplasmy in the affected individuals ranged from 86% in muscle to undetectable in hair (PS4_supporting; PMIDs: 14967777, 15111688). This variant occurred de novo in one individual (absent in blood, urine, hair, and muscle from mother as well as two sisters, two maternal aunts, and two maternal uncles; PM6, PMID: 15111688). The computational predictor MitoTIP suggests this variant is pathogenic (93.5 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in muscle fibers from both affected individuals, supporting the functional impact of this variant (PS3_supporting). In one individual, the mean heteroplasmy level in abnormal fibers was 90% ± 2% (n=22) and in normal fibers was 58% ± 6% (n=15; P = 0.007). Furthermore, in ragged red fibers, the mean heteroplasmy level was 94% (PMID: 14967777). In the other individual, the mean heteroplasmy level in COX-deficient fibers was 94.6 ± 1.53% (n = 12) and in COX-positive fibers was 32.5 ± 6.18% (n = 10; p < 0.0001; PMID: 15111688). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6, PM2_supporting, PP3, PS3_supporting. |
| Wong Mito Lab, |
RCV000851013 | SCV000993247 | pathogenic | MELAS syndrome | 2019-07-12 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.12147G>A variant in MT-TH gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PM8, PM9 |
| Mendelics | RCV002247294 | SCV002517694 | pathogenic | Mitochondrial disease | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000010234 | SCV000030458 | pathogenic | MERRF/MELAS overlap syndrome | 2004-04-27 | no assertion criteria provided | literature only | |
| Gene |
RCV000851013 | SCV004042627 | not provided | MELAS syndrome | no assertion provided | literature only |