rs387906420
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_ModeratePP1_ModeratePP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The m.616T>C variant in MT-TF has been reported in at least 12 individuals from six families with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life with delays or seizures at 10 months old to late teenage years with renal disease or epilepsy). Several individuals had chronic kidney disease or renal failure; some even had transplants with non-recurrence of disease post-transplant. Other symptoms reported include developmental delay, epilepsy, status epilepticus (EPC), and myoclonus. Muscle biopsy revealed COX negative fibers. Heteroplasmy levels were the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Of note, some healthy family members had the variant at lower heteroplasmy levels but in at least one healthy family member, the variant was present at a heteroplasmy level as high as 92% (PS4_moderate; PMIDs: 31722346, 28267784, 20142618). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower or undetectable levels of the variant (PP1_moderate; PMIDs: 31722346, 28267784, 20142618). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There is one cybrid study for this variant however the cybrid also had another mtDNA variant precluding scoring for PS3. There are no single fiber studies or other functional assays reported for this variant. The computational predictor MitoTIP suggests this variant is pathogenic (83.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120552/MONDO:0044970/014
Frequency
Consequence
unassigned_transcript_4784 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNF | unassigned_transcript_4784 | c.40T>C | p.Cys14Arg | missense_variant | Exon 1 of 1 | |||
| RNR1 | unassigned_transcript_4785 | n.-32T>C | upstream_gene_variant |
Ensembl
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:2
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The m.616T>C variant in MT-TF has been reported in at least 12 individuals from six families with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life with delays or seizures at 10 months old to late teenage years with renal disease or epilepsy). Several individuals had chronic kidney disease or renal failure; some even had transplants with non-recurrence of disease post-transplant. Other symptoms reported include developmental delay, epilepsy, status epilepticus (EPC), and myoclonus. Muscle biopsy revealed COX negative fibers. Heteroplasmy levels were the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Of note, some healthy family members had the variant at lower heteroplasmy levels but in at least one healthy family member, the variant was present at a heteroplasmy level as high as 92% (PS4_moderate; PMIDs: 31722346, 28267784, 20142618). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower or undetectable levels of the variant (PP1_moderate; PMIDs: 31722346, 28267784, 20142618). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There is one cybrid study for this variant however the cybrid also had another mtDNA variant precluding scoring for PS3. There are no single fiber studies or other functional assays reported for this variant. The computational predictor MitoTIP suggests this variant is pathogenic (83.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. -
Interstitial nephritis Pathogenic:1
The m.616T>C variant was observed in 1 family affected by tubulo-interstitial kidney disease (Connor et al. 2017). At least two members of this family were later found to additionally suffer from hypomagnesemia and hypokalemia.(Viering et al. 2021) The homoplasmic variant cosegregated with disease. The variant was scored as pathogenic based on the system published by Wong et al. (2020): PS5, PM7, PM9, PM10. -
Epilepsy, mitochondrial Pathogenic:1
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MELAS syndrome Pathogenic:1
The NC_012920.1:m.616T>C variant in MT-TF 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: PS5, PM7, PM9, PM10 -
Computational scores
Source: