Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000681108 | SCV000808565 | likely pathogenic | not provided | 2018-02-12 | criteria provided, single submitter | clinical testing | The I46T variant in the HRAS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The I46T variant is not observed in large population cohorts (Lek et al., 2016). The I46T 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret I46T as a likely pathogenic variant. |
Labcorp Genetics |
RCV001861890 | SCV002111088 | uncertain significance | Costello syndrome | 2023-09-29 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the HRAS protein (p.Ile46Thr). This variant is not present in population databases (gnomAD no frequency). 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. 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 HRAS protein function. ClinVar contains an entry for this variant (Variation ID: 561731). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. |