ClinVar

Description

The m.15242G>A (p.Gly166Ter) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This individual had exercise intolerance, lactic acidosis, encephalomyopathy, hallucinations, depression, memory loss, and seizures. The variant was present at 87-92% heteroplasmy in muscle, 0.7% in blood, and 4-14% in hair roots (PMID:11047755). This variant was also seen in her unaffected sister (<0.2% in blood) and was undetectable in blood from her healthy mother, however this cannot be considered evidence for segregation nor de novo occurrence as the variant was detected at very low levels in the proband’s blood. This variant causes a premature stop in the MT-CYB gene (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in ragged red fibers (89±8%) than in non-ragged red fibers (66±26%) p<0.0001 (PS3_supporting, PMID: 11047755). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PVS1_strong, PS3_supporting.