ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.806T>G (p.Met269Arg) (rs137852813)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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has been identified in seven individuals affected with the clinical features of Noonan syndrome by o ur laboratory (LMM unpublished data).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 (
GeneDx RCV000157691 SCV000209102 pathogenic not provided 2021-03-31 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 17143285, 25862627, 24803665, 26280111, 17586837, 23885229, 22420426, 17143282, 21387466, 29165300, 29074966, 18854871, 30417923)
Invitae RCV000554031 SCV000659154 pathogenic Rasopathy 2020-09-10 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.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856805 SCV000999371 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000157691 SCV001249220 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000554031 SCV001432038 pathogenic Rasopathy 2020-08-31 criteria provided, single submitter clinical testing Variant summary: SOS1 c.806T>G (p.Met269Arg) 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 251358 control chromosomes. c.806T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome (examples- Roberts_2007, Tartaglia_2007, Zenker_2007, Ko_2008, Neumann_2009,Lepri_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that the variant conveys a gain-of-function to the protein, as higher levels of RAS-GTP and ERK activation were observed in cells with the variant (example- Roberts_2007). 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. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000013730 SCV000033977 pathogenic Noonan syndrome 4 2007-01-01 no assertion criteria provided literature only
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157691 SCV000207675 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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