ClinVar

Description

Variant summary: NDUFV1 c.166T>C (p.Ser56Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251496 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NDUFV1 causing Leigh Syndrome (5.2e-05 vs 0.0013), allowing no conclusion about variant significance. c.166T>C has been reported in the literature in individuals affected with Mitochondrial Complex I Deficiency (Koene_2012, De La Vega_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25615419, 34645491, 35482023, 22644603, 23562761, 35482246, 26345448, 29948731). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=3) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.