ClinVar

Description

The m.12425del (p.N30TfsX7) variant in MT-ND5 has been reported in one individual to date, in a girl with mitochondrial myopathy and renal failure. In childhood, she was found to have impaired growth, mild metabolic acidosis, and elevated creatinine. After several years, her renal function declined, and she had daily vomiting and weight loss. Additionally, she had exercise intolerance and mild pigmentary retinopathy. She had received a donor kidney at the time of report and did well. She had persistently elevated blood lactate (5.1-5.9 mmol/L, normal 0.7-2.1). A renal biopsy showed glomerulocystic disease with significant atrophy and fibrosis. A muscle biopsy showed mild variation in fiber size with occasional atrophic, angulated fibers but no evidence of inflammatory changes and mild increase in lipid content. COX and SDH histochemistry revealed moderately increased enzyme activities in subsarcolemmal areas, subsarcolemmal mitochondrial accumulation, reduced complex I activity (with normal complex II+III and complex IV activities) and reduced fully assembled complex I. The variant was present at 85% heteroplasmy in muscle, 14% in blood, 19% in urine, and 22% in buccal sample (PMID: 20018511). As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and urine samples from her healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.007%; Helix's 196,554 sequences: AF=0.0005%; and gnomAD v3.1.2: AF=0.016% as this is heteroplasmic in 4 individuals). Given the frequency of this variant, it does not meet PM2 criterion. This variant results in a frameshift in codon 30, introducing a premature stop codon which predicts a truncation of the MT-ND5 protein from its full-length of 604 amino acids to 35 amino acids (PVS1_strong). 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 however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given biochemical evidence in the proband’s muscle is consistent with the predicted effect of this variant and because the variant is present at low heteroplasmy levels in the sequences in gnomAD v3.1.2. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PVS1_strong.