Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481064 | SCV000571281 | likely pathogenic | not provided | 2016-10-25 | criteria provided, single submitter | clinical testing | To our knowledge, the R377W variant in the STS gene has not been reported previously as a pathogenic variant, nor as a benign variant. It was not observed in approximately 6,500 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 R377W 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. Missense variants in nearby residues (W372R/S, G380R) have been reported in the Human Gene Mutation Database in association with ichthyosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the R377W variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Labcorp Genetics |
RCV000481064 | SCV003243716 | uncertain significance | not provided | 2023-05-17 | 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 377 of the STS protein (p.Arg377Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked ichthyosis (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 421936). 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 STS protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |