Variant: m.616T>C

CA120552

9576 (ClinVar)

Gene: MT-TF

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 76f3ee2d-60c9-4ad8-b104-1c2463b58a5c

Approved on: 2022-06-30

Published on: 2022-06-30

HGVS expressions

NC_012920.1:m.616T>C
J01415.2:m.616T>C

Likely Pathogenic

• Met criteria codes: PP3 PS4_Moderate PP1_Moderate PM2_Supporting

• Not Met criteria codes: PS3 PS2 PM6

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

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.

Met criteria codes

• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (83.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3).
• PS4_Moderate: 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).
• PP1_Moderate: 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).
• PM2_Supporting: Absent in gnomAD, Helix, and Mitomap after removal of affected cases.

Not Met criteria codes

• PS3: 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.
• PS2: There are no reports of de novo occurrence of this variant.
• PM6: There are no reports of de novo occurrence of this variant.