Submissions for variant NM_006939.4(SOS2):c.800T>A (p.Met267Lys)

dbSNP: rs797045167

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics Laboratory, Instituto de Ciencias en Reproduccion Humana	RCV000191031	SCV001162783	pathogenic	Noonan syndrome 9	2019-12-30	criteria provided, single submitter	research	This missense variant replaces methionine with lysine at codon 267 of the SOS2 protein (p.Met267Lys). This variant has been previously reported as pathogenic in a Brazilian patient with Noonan syndrome (PMID: 25795793). ACMG interpretation was pathogenic and the criteria used were: PS1 based on other aminoacids change M267R and M267T reported as pathogenic/likely pathogenic according ACMG criteria in Clinvar. PM1 because p.M267K is located in DH domain that is a well-established functional domain with other pathogenic variants. PM2 based on variant is not on gnomAD v2.1.1 and v3 and TOPMed Freeze 5. PP3 supporting disease causing by DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. PP4 because the phenotype is highly suggestive a single disease, in this case a Rasopathy.
Invitae	RCV000191031	SCV001396805	pathogenic	Noonan syndrome 9	2019-05-02	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: 26173643). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual affected with Noonan syndrome (PMID: 25795793). ClinVar contains an entry for this variant (Variation ID: 209092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 267 of the SOS2 protein (p.Met267Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine.
Department of Human Genetics, University Hospital Magdeburg	RCV000191031	SCV001426180	pathogenic	Noonan syndrome 9	2020-07-02	criteria provided, single submitter	clinical testing	This variant 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 variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6). The REVEL Score of this variant is 0.802 (PP3) and the variant has been classified as pathogenic in ClinVar (PP5).
Genome-Nilou Lab	RCV000191031	SCV002763115	pathogenic	Noonan syndrome 9		criteria provided, single submitter	clinical testing
GeneDx	RCV003320592	SCV004025864	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25795793, 27942422, 33750022, 30707178, 34006472, 35683512, 32788663, 26173643, 29696775)
OMIM	RCV000191031	SCV000246011	pathogenic	Noonan syndrome 9	2015-06-01	no assertion criteria provided	literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000191031	SCV001482366	pathogenic	Noonan syndrome 9	2019-05-31	no assertion criteria provided	research