ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.800T>G (p.Met267Arg) (rs797045167)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699741 SCV000828465 likely pathogenic Noonan syndrome 9 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 267 of the SOS2 protein (p.Met267Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Noonan syndrome (PMID: 26173643) Experimental studies have shown that this missense change results in high levels of RAS, MEK, and ERK function, consistent with the known gain-of-function mechanism of disease (PMID: 26173643). The p.Met267 amino acid residue in SOS2 has been determined to be clinically significant (PMID: 25795793). This suggests that variants that disrupt this residue are likely to be causative of disease. 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.
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 likely pathogenic Rasopathy 2020-10-19 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 individuals affected with Noonan Syndrome (Cordeddu_2015, Bessis_2019). These data indicate that the variant may be associated with disease. In addition, another missense in the same residue (p.M267K) has been found in individuals affected with Noonan Syndrome suggesting this residue is clinical important (Yamamoto_2015, Ding_2019). At least one functional study reports this variant increases RAS and MEK/ERK activation (Cordeddu_2015). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001251214 SCV001426700 pathogenic Noonan syndrome no assertion criteria provided clinical testing
GeneDx RCV001575734 SCV001802788 pathogenic not provided 2020-08-05 no assertion criteria provided 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 (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30417923, 29696775, 27942422, 26173643, 30707178)

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