ClinVar Genomic variation as it relates to human health

The c.1268C>T;p.(Thr423Met) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 14056 ; PMID: 30090137; 10080174) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26345448) - PS3_supporting. The variant is present at low allele frequencies population databases (rs121913659– gnomAD 0.0003295%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Thr423Met) was detected in trans with a Pathogenic variant (PMID: 30090137; 10080174) and found as compound heterozygous with another variant classified as Pathogenic (knowing the phase of each variant), in the analyzed case - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 10080174) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014056, PMID:10080174, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 14662656, PS3_M).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10080174, PM3_M). and co-segregated with Mitochondrial complex I deficiency, nuclear type 4 in multiple affected family members (PMID: 10080174, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.859, PP3_P). A missense variant is a common mechanism associated with Mitochondrial complex I deficiency (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: NDUFV1 c.1268C>T (p.Thr423Met) results in a non-conservative amino acid change located in the NADH-ubiquinone oxidoreductase 51kDa subunit, iron-sulphur binding domain (IPR019575) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251318 control chromosomes. c.1268C>T has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple individuals affected with Leigh Syndrome (example, PMID 33083013, 34716721, 10080174). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID 26345448). The most pronounced variant effect results in absence of detectable complex I in an apparently homozygous (by cDNA sequencing), but compound heterozygous genotype due to a nonsense variant on the other allele that was not expressed. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 423 of the NDUFV1 protein (p.Thr423Met). This variant is present in population databases (rs121913659, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 10080174, 22644603, 30090137, 31665838). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14056). 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 expected to disrupt NDUFV1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17383918, 19041632, 17289351, 18435906, 18353897, 29948731, 30090137, 11579423, 20153825, 11181577, 16120313, 34807224, 31665838, 10080174, 21696386, 17600689, 10649489, 19703648, 19255735, 15901599, 18295330, 10330338, 29395179, 24704045, 11112787, 14662656, 16213125, 24524415, 30429455, 15981016, 22033105, 10862082, 10885663, 23631824, 22142868, 30055843, 26345448, 31216405, 33083013)