ClinVar

Description

The m.7637G>A (p.E18K) variant in MT-CO2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual with Parkinson disease with haplogroup Uk1 (PMID: 19076426). There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 2/59,389 (0.003%). The frequency in gnomAD v3.1.2 is 6/56,427 (0.011%). This includes three homoplasmic occurrences (two European, one African/African American, haplogroups T, J, L2) and three heteroplasmic occurrences (two European, one African/African American; haplogroups K, L3, U; one with 10-20% heteroplasmy, one with 30-40% heteroplasmy, one with 60-70% heteroplasmy; two individuals in 70-75-year-old range with details not provided on other individuals). The frequency in the Helix dataset is 16/195,983 (0.008%) including 12 homoplasmic occurrences (haplogroups T=6, H=3, A=1, C=1, L2=1) and four heteroplasmic occurrences (haplogroup J=1, K=1, L3=1, T=1). Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). There are no cybrids, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.91 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP3.