Submissions for variant NM_005633.4(SOS1):c.1310T>G (p.Ile437Ser)

dbSNP: rs397517150

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159165	SCV000209110	pathogenic	not provided	2014-07-24	criteria provided, single submitter	clinical testing	p.Ile437Ser (ATT>AGT): c.1310 T>G in exon 10 of the SOS1 gene (NM_005633.3). The I437S mutation 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. I437S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense mutations in the same and nearby residues (G434R, I437N, I437T, C441Y) have been reported in association with Noonan syndrome, supporting the functional importance of this region of the protein. The variant is found in NOONAN panel(s).
Invitae	RCV001379728	SCV001577577	likely pathogenic	RASopathy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 437 of the SOS1 protein (p.Ile437Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181551). 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 SOS1 protein function with a positive predictive value of 80%. This variant disrupts the p.Ile437 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21387466, 24451042). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV002467633	SCV002763427	likely pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261079	SCV001438481	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing