Submissions for variant NM_006939.4(SOS2):c.800T>C (p.Met267Thr)

dbSNP: rs797045167

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414175	SCV000491679	pathogenic	not provided	2017-11-17	criteria provided, single submitter	clinical testing	The M267T variant in the SOS2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a different missense variant in the same residue, M267K, was identified as a de novo change in a patient with Noonan syndrome (Yamamoto et al., 2015). A second missense variant in the same residue, M267R, was identified in two individuals with Noonan syndrome, and functional studies of M267R indicate that it promotes enhanced phosphorylation of ERK (Cordeddu et al., 2015). The M267T variant was not observed 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. The M267T 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. We interpret M267T as a pathogenic variant
Department of Human Genetics, University Hospital Magdeburg	RCV001250768	SCV001426181	pathogenic	Noonan syndrome 9	2020-07-02	criteria provided, single submitter	clinical testing	This variant has been previously reported as pathogenic (PS1). It is absent from gnomAD (PM2). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6). The REVEL Score of this variant is 0.868 (PP3) and the variant has been classified as pathogenic in ClinVar (PP5).
Invitae	RCV001250768	SCV002227833	pathogenic	Noonan syndrome 9	2023-06-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met267 amino acid residue in SOS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25795793, 26173643). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SOS2 protein function. ClinVar contains an entry for this variant (Variation ID: 373114). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 267 of the SOS2 protein (p.Met267Thr).
Genome-Nilou Lab	RCV001250768	SCV002763114	pathogenic	Noonan syndrome 9		criteria provided, single submitter	clinical testing