Submissions for variant NM_006939.4(SOS2):c.800T>G (p.Met267Arg)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000699741	SCV000828465	pathogenic	Noonan syndrome 9	2023-08-09	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). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOS2 function (PMID: 26173643). 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: 577079). This missense change has been observed in individuals with Noonan syndrome (PMID: 26173643; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 267 of the SOS2 protein (p.Met267Arg).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000699741	SCV001366232	pathogenic	Noonan syndrome 9	2020-03-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP3.
Department of Human Genetics, University Hospital Magdeburg	RCV000699741	SCV001426179	pathogenic	Noonan syndrome 9	2020-07-02	criteria provided, single submitter	clinical testing	This variant has been previously reported as pathogenic including well-established functional studies (PS1 and PS3). It is absent from gnomAD (PM2). Variants at the analogous position in SOS1 (c.806T>G and c.806T>C) have been classified as pathogenic (PM5_Strong). The REVEL score of this variant is 0.919 (PP3) and the variant has been classified as likely pathogenic in ClinVar (PP5).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264473	SCV001442647	pathogenic	RASopathy	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.800T>G (p.Met267Arg) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes (gnomAD). c.800T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome (Cordeddu_2015, Bessis_2019, Lissewski_2021, Lallar_2021). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant increases RAS and MEK/ERK activation (Cordeddu_2015). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001575734	SCV001802788	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate variant promotes enhanced phosphorylation of extracellular signal-regulated kinase (ERK) compared to wild type protein (Cordeddu et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30707178, 26173643, 27942422, 29696775, 30417923, 32788663)
Genome-Nilou Lab	RCV000699741	SCV002763113	likely pathogenic	Noonan syndrome 9		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411629	SCV004108102	pathogenic	SOS2-related condition	2023-11-29	criteria provided, single submitter	clinical testing	The SOS2 c.800T>G variant is predicted to result in the amino acid substitution p.Met267Arg. This variant as been reported in multiple individuals with Noonan syndrome, being documented as occurring de novo in at least one individual (Cordeddu et al. 2015. PubMed ID: 26173643; Lissewski et al. 2020. PubMed ID: 32788663). This variant has not been reported in a large population database, indicating this variant is rare. Alternative substitutions (Lys, Thr) at this amino acid position have also been reported as causative for Noonan syndrome (Yamamoto et al. 2015. PubMed ID: 25795793; Lissewski et al. 2021. PubMed ID: 32788663). This variant is interpreted as pathogenic.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001251214	SCV001426700	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing