ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.806T>G (p.Met269Arg) (rs137852813)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157691 SCV000209102 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing The M269R variant has been published many times, including as a confirmed de novo pathogenic variant, in association with Noonan syndrome (examples see Tartaglia et al., 2007; Roberts et al., 2007; Neumann et al., 2009). In vitro functional studies demonstrated that the M269R variant results in increased EGF-evoked ERK activation in comparison to wild-type (Roberts et al., 2007). The M269R variant is not observed in large population cohorts (Lek et al., 2016). The M269R 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same residue (M269T) and in a nearby residue (T266K) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret this variant as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157691 SCV000207675 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Invitae RCV000554031 SCV000659154 pathogenic Rasopathy 2017-09-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 269 of the SOS1 protein (p.Met269Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (rs137852813, ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome (PMID: 17143282, 17143285, 17586837, 19020799, 22420426, 23885229). In at least one of these individuals, the variant was observed to be de novo (PMID: 17143282). ClinVar contains an entry for this variant (Variation ID: 12870). Experimental studies have shown that this missense change disrupts SOS1 auto-inhibition, leading to increased activity in vitro (PMID: 17143285, 20683980). A different missense substitution at this codon (p.Met269Thr) has also been determined to be pathogenic (PMID: 20683980, 19953625). This suggests that the methionine residue is critical for SOS1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211854 SCV000062250 pathogenic Noonan syndrome 2013-07-17 criteria provided, single submitter clinical testing The Met269Arg variant has been identified in several individuals with clinical f eatures of Noonan syndrome in the literature (Ko 2008, Tartaglia 2007, Roberts 2 007). This variant was determined to have occurred de novo in at least one of th ese individuals (Tartaglia 2007). In addition, this variant has been identified in seven individuals affected with the clinical features of Noonan syndrome by o ur laboratory (LMM unpublished data). This variant was also absent in large popu lation studies. In summary, the Met269Arg variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM).
OMIM RCV000013730 SCV000033977 pathogenic Noonan syndrome 4 2007-01-01 no assertion criteria provided literature only

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