Submissions for variant NM_005343.4(HRAS):c.317C>G (p.Ser106Trp)

dbSNP: rs730880462

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157921	SCV000207856	uncertain significance	not provided	2014-07-29	criteria provided, single submitter	clinical testing	p.Ser106Trp (TCG>TGG): c.317 C>G in exon 4 of the HRAS gene (NM_005343.2). The S106W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Mutations in the HRAS gene are associated with Noonan spectrum disorders, including Costello syndrome. Noonan syndrome is a developmental disorder characterized by short stature, dysmorphic facial features, cardiac defects and developmental delay (Tartaglia M et al., 2002; Allanson J et al., 2011). In addition to features of Noonan syndrome, individuals with Costello syndrome typically have musculoskeletal abnormalities and tumor predisposition (Gripp K and Lin A, 2012). Hypertrophic cardiomyopathy (HCM) and arrhythmia have been reported in individuals with Costello syndrome, however the percentage of individuals with HCM and/or arrhythmia is currently unknown. The S106W variant 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 S106W 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 and this substitution occurs at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV000816581	SCV000957098	uncertain significance	Costello syndrome	2023-06-23	criteria provided, single submitter	clinical testing	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 not expected to disrupt HRAS protein function. ClinVar contains an entry for this variant (Variation ID: 180850). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 106 of the HRAS protein (p.Ser106Trp).
Ambry Genetics	RCV002321658	SCV002609290	uncertain significance	Cardiovascular phenotype	2022-02-02	criteria provided, single submitter	clinical testing	The p.S106W variant (also known as c.317C>G), located in coding exon 3 of the HRAS gene, results from a C to G substitution at nucleotide position 317. The serine at codon 106 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.