ClinVar Genomic variation as it relates to human health

Variant summary: PUS1 c.430C>T (p.Arg144Trp) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved amino acid within the catalytic center of the protein (Bykhovskaya_2004). 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 7.9e-06 in 252926 control chromosomes. c.430C>T has been reported in the literature in multiple individuals affected with Mitochondrial myopathy and sideroblastic anaemia, with evidence of cosegregation (Bykhovskaya_2004, Zeharia_2005). These data indicate that the variant is very likely to be associated with disease. Patient derived cell lines and in vitro functional assays suggest this substitution results in a loss of pseudouridine synthase activity (Patton_2005, Sibert_2008). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 144 of the PUS1 protein (p.Arg144Trp). This variant is present in population databases (rs104894371, gnomAD 0.007%). This missense change has been observed in individuals with mitochondrial myopathy and sideroblastic anemia (MLASA) (PMID: 15108122, 15971356). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2536). 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 PUS1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The observed missense c.430C>T (p.Arg144Trp) variant in PUS1 gene has been reported previously in individuals affected with PUS1-related disorders (Bykhovskaya et al., 2004). It has also been observed to segregate with disease in related individuals. Patient derived cell lines and in vitro functional assays suggest this substitution results in a loss of pseudouridine synthase activity (Patton et al., 2005; Sibert et al., 2008). The p.Arg144Trp variant is present with allele frequency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg144Trp in PUS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 144 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.