ClinVar

Description

Variant summary: NDUFAF2 c.114C>G (p.Tyr38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position has been classified as pathogenic by our laboratory (e.g. c.139C>T, p.Arg47X; c.221G>A, p.Trp74X). The variant allele was found at a frequency of 5.4e-05 in 277122 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.114C>G, has been reported in the literature in one homozygote individual affected with Leigh Syndrome (Hoefs_2009). These data indicate that the variant may be associated with disease. The same publication reports experimental evidence showing no NDUFAF2 protein expression in patient's fibroblasts and a marked decrease in complex I activity (to 21-23% of the lowest control value). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic.