ClinVar Genomic variation as it relates to human health

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

Variant summary: NDUFB3 c.64T>C (p.Trp22Arg) results in a non-conservative amino acid change in 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 0.00085 in 250986 control chromosomes. c.64T>C has been reported in the literature in individuals affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 25 or related disorders. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that protein with this variant could not rescue NDUFB3 deficiency. Nine 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 variant segregates with disease and has been identified in multiple affected individuals with clinical features associated with this gene (PMID: 22277967, 22499348, 27091925). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 22277967, 22499348, 27091925). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 22 of the NDUFB3 protein (p.Trp22Arg). This variant is present in population databases (rs142609245, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 22277967, 27091925). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252575). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFB3 function (PMID: 27091925). For these reasons, this variant has been classified as Pathogenic.

Expression of W22R into patient fibroblasts failed to rescue mitochondrial complex I deficiency, while expression of wild-type NDUFB3 rescued complex I activity (Haack et al., 2012); This variant is associated with the following publications: (PMID: 22277967, 22499348, 27091925, 26795593, 31000363, 31589614)

A Heterozygous Missense variant c.64T>C in Exon 2 of the NDUFB3 gene that results in the amino acid substitution p.Trp22Arg was identified. The observed variant has a minor allele frequency of 0.00085/0.00080% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic (variant ID: 252575). This variant was reported among the patients for infantile Mitochondrial Disease (Calvo SE et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

The c.64T>C (p.W22R) alteration is located in exon 2 (coding exon 1) of the NDUFB3 gene. This alteration results from a T to C substitution at nucleotide position 64, causing the tryptophan (W) at amino acid position 22 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.08% (239/282372) total alleles studied. The highest observed frequency was 0.14% (178/128812) of European (non-Finnish) alleles. This mutation was reported homozygous in an individual with severe intrauterine growth restriction, failure to thrive, hypotonia, and recurrent episodes of metabolic acidosis (Calvo, 2012). It was also identified compound heterozygous with a nonsense variant in an individual with hypotonia, developmental delay, and lactic acidosis (Haack, 2012). Another study of 8 families with individuals homozygous for this variant showed a distinctive facial appearance, short stature, and a more mild biochemical and clinical phenotype, although some patients presented with acute metabolic crises (Alston, 2016). Complementation studies demonstrated that the p.W22R alteration produced decreased complex I activity (Calvo, 2012; Haack, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

NDUFB3: PP1:Moderate, PP4:Moderate, PS3:Moderate