Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001384611 | SCV001584176 | pathogenic | not provided | 2023-11-29 | criteria provided, single submitter | clinical testing | 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000002645 | SCV002766471 | pathogenic | Myopathy, lactic acidosis, and sideroblastic anemia 1 | 2022-11-29 | criteria provided, single submitter | clinical testing | 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. |
| Baylor Genetics | RCV000002645 | SCV004207180 | likely pathogenic | Myopathy, lactic acidosis, and sideroblastic anemia 1 | 2023-09-24 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000002645 | SCV000022803 | pathogenic | Myopathy, lactic acidosis, and sideroblastic anemia 1 | 2004-06-01 | no assertion criteria provided | literature only |