Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000233989 | SCV000291949 | uncertain significance | not provided | 2014-08-11 | criteria provided, single submitter | clinical testing | To our knowledge, the R28W variant has neither been published as a mutation, nor reported as a benign polymorphism. It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R28W 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 conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution does not occur in the coiled-coil domain region, the region where definitive PSTPIP1 mutations have been identified to date. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. |
| Invitae | RCV001062059 | SCV001226831 | uncertain significance | Pyogenic arthritis-pyoderma gangrenosum-acne syndrome | 2023-10-17 | 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 28 of the PSTPIP1 protein (p.Arg28Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PSTPIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 242300). 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 PSTPIP1 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. |