Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000154576 | SCV000204249 | uncertain significance | not specified | 2011-04-15 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Arg169Trp varia nt has not been previously reported in the literature. This variant has been ide ntified in our laboratory in one other individual and that individual's reported ly unaffected parent. This suggests that this variant does not affect the normal function of HRAS. However, since individuals with Noonan spectrum disorders can have variable expressivity, we can not determine the clinical significance of t his variant conclusively at this time. |
Gene |
RCV000154576 | SCV000490889 | uncertain significance | not specified | 2015-06-16 | criteria provided, single submitter | clinical testing | Although the R169W variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge, it has been reported by an outside laboratory as a variant of uncertain significance (Landrum et al., 2014). The R169W variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the R169W 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. Furthermore, this substitution occurs at a position that is conserved across species. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Labcorp Genetics |
RCV000803493 | SCV000943368 | uncertain significance | Costello syndrome | 2023-11-10 | 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 169 of the HRAS protein (p.Arg169Trp). This variant is present in population databases (rs151229168, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 177918). 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 not expected to disrupt HRAS protein function with a negative predictive value of 95%. 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. |
Ambry Genetics | RCV002345496 | SCV002645912 | uncertain significance | Cardiovascular phenotype | 2021-08-31 | criteria provided, single submitter | clinical testing | The p.R169W variant (also known as c.505C>T), located in coding exon 4 of the HRAS gene, results from a C to T substitution at nucleotide position 505. The arginine at codon 169 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV002505170 | SCV002812902 | uncertain significance | Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2 | 2021-09-07 | criteria provided, single submitter | clinical testing |