Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003153298 | SCV003842284 | likely pathogenic | Mitochondrial disease | 2022-08-08 | reviewed by expert panel | curation | The m.3256C>T variant in MT-TL1 has been reported in four individuals in the literature and an additional four cases were seen by experts on this panel. Affected individuals had primary mitochondrial disease with variable features including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) phenotype, neurologic involvement (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, seizures, ataxia, myoclonus); neuromuscular involvement (muscle atrophy, progressive myopathy); cardiac involvement (cardiac failure); ophthalmologic involvement (ophthalmoplegia, ptosis, central vision loss); ENT involvement (hearing loss); endocrine involvement (hashimoto thyroiditis, diabetes mellitus); lab abnormalities (elevated blood and CSF lactate and pyruvate); and brain imaging findings (progressive brain atrophy); with heteroplasmy levels in multiple tissues ranging from 8% - 98% (PS4_moderate; PMIDs: 19941338, 10953207, 7804130, 8254046). This variant segregated with disease in a single reported family as the proband’s healthy sister had undetectable levels of variant in blood; the proband’s mother was decreased; and the proband was heteroplasmic for the variant in numerous tissues: 64% (muscle), 8% (white blood cells), 48% (first passage cultured fibroblasts), and 18% (hair roots) (PP1; PMID: 8254046). There are no reports of de novo occurrences of this variant to our knowledge. Ragged red fiber (RRF) analysis in muscle noted only partially impaired COX activity. However, when analyzed for levels of mutant genomes, RRFs were essentially homoplasmic for mutant mtDNAs (range 94-97%). Normal (non-RRFs) had much lower levels of mutant genomes (34-75%). The percentage of mutant mtDNA in total the muscle was 64% (PS3_supporting: PMID: 8254046). This variant is absent from Mitomap's 51,863 sequences (AF=0.00%); Helix's 196,554 sequences (AF=0.00%); and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 93.70%, as does HmtVar with a score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of pathogenic given the overwhelming evidence of pathogenicity (strong single fiber studies, absent in population databases and present in eight individuals with features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PP1, PS3_supporting |
| Wong Mito Lab, |
RCV000850697 | SCV000992929 | pathogenic | MELAS syndrome | 2019-07-12 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.3256C>T variant in MT-TL1 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, PS5, PM7 |
| OMIM | RCV000010213 | SCV000030437 | pathogenic | MERRF syndrome | 1998-03-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000010214 | SCV000030438 | pathogenic | Diabetes mellitus, noninsulin-dependent, maternally transmitted | 1998-03-01 | no assertion criteria provided | literature only | |
| Gene |
RCV000850697 | SCV004042645 | not provided | MELAS syndrome | no assertion provided | literature only |