ClinVar

Description

The m.3733G>A (p.E143K) variant in MT-ND1 has been reported in 10 individuals with features of primary mitochondrial disease from 4 families. Affected individuals had features consistent with LHON and LHON-plus (PS4_moderate; PMIDs: 15505787, 27177320, 29387390). There are no reports of de novo occurrences of this variant. Segregation was only seen in one family, with healthy mother having lower heteroplasmy levels than affected child (PMID: 15505787), however this does not meet criteria for PP1_supporting (minimum 2 segregations). There are 2 occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease, and this variant is absent in gnomAD v3.1.2 and in Helix dataset (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (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 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3.