ClinVar

Description

The m.14674T>G variant in MT-TE has been reported in two affected individuals with reversible infantile respiratory chain deficiency from a Japanese cohort (PMID: 21194154). One girl presented with congenital myopathy and muscle weakness, and muscle biopsy at age 8 months showed ragged red fibers. Blood and cerebrospinal fluid (CSF) lactate levels were normal. By age 15 years, she had no persistent medical concerns. The variant was present at homoplasmy in muscle. The other reported individual, also a girl, presented with mitochondrial myopathy and failure to thrive. Muscle biopsy at age 5 months showed ragged red fibers and reduced respiratory chain enzyme activities. She had elevated blood creatine kinase and lactate, and elevated CSF lactate. By age 11 years, she had mild exercise intolerance only. The variant was present at homoplasmy in muscle. There was no mention of testing in family members of either proband. There are no reported de novo occurrences to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are inconsistent for this variant as MitoTIP suggests this variant is benign (29.4 percentile) and HmtVAR predicts it to be deleterious (0.4). Another variant at this position was classified as likely pathogenic by this Expert Panel (m.14674T>C, PM5_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM5_supporting.