ClinVar Genomic variation as it relates to human health

The S56P variant in the NDUFV1 gene has been previously reported in the compound heterozygous state with a pathogenic missense variant in an individual with mitochondrial complex I deficiency (Koene et al., 2012). This variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. The S56P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The S56P variant is a strong candidate for a pathogenic variant.

This variant has been reported in the compound heterozygous state with a pathogenic missense variant in an individual with mitochondrial complex I deficiency (PMID: 22644603). This variant has been reported in the public SNP databases; however with a very low frequency. Based on the overall evidence, we classified this variant as likely pathogenic.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 56 of the NDUFV1 protein (p.Ser56Pro). This variant is present in population databases (rs201727685, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 22644603). ClinVar contains an entry for this variant (Variation ID: 372715). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NDUFV1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The NDUFV1 c.166T>C variant is predicted to result in the amino acid substitution p.Ser56Pro. This variant was reported, along with a second missense variant, in two individuals with suspected mitochondrial disease and complex I deficiency (Koene et al. 2012. PubMed ID: 22644603, supplementary data; Clark et al. 2019. PubMed ID: 31019026, supplementary data). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-67376033-T-C). Although we suspect that NDUFV1 c.166T>C (p.Ser56Pro) may be pathogenic, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.

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.