ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.806T>C (p.Met269Thr) (rs137852813)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000208414 SCV000616384 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.806T>C (p.Met269Thr) variant in SOS1 has been reported in the literature in at least 2 unconfirmed and 1 confirmed de novo occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837; 19953625, 20683980). It has also been reported as a confirmed de novo occurrence in a patient with clinical features of a RASoapthy (PMID: 20683980). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS2_VeryStrong.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000208414 SCV000062249 pathogenic Noonan syndrome 2015-04-27 criteria provided, single submitter clinical testing The p.Met269Thr variant has been reported in >10 individuals with clinical featu res of Noonan syndrome (Ko 2008, Longoni 2010, Denayer 2010, Lepri 2011, Zenker 2007; LMM unpublished data). In three of these probands, the variant occurred de novo (Zenker 2007, Denayer 2010, Longoni 2010). It was absent from large popula tion studies. In summary, this variant meets our criteria to be classified as pa thogenic for Noonan syndrome in an autosomal dominant manner (http://www.partner s.org/personalizedmedicine/LMM) based upon absence from controls and de novo occ urrences.
GeneDx RCV000157690 SCV000209101 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing The M269T missense pathogenic variant in the SOS1 gene is a non-conservative amino acid substitution that occurs within the highly conserved Dbl-homology domain. The M269T variant has been reported multiple individuals, of which at least 3 were observed to be de novo occurrences, with clinical features of Noonan syndrome (Ko et al., 2008, Longoni et al., 2010, Denayer et al., 2010, Lepri et al., 2011, Zenker et al., 2007). In addition, functional analyses of another missense pathogenic variant at this residue (Met269Arg) indicate abnormally hyperactive cellular Ras signaling (Roberts et al., 2007). The M269T variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider M269T to be pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000157690 SCV000263042 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000208414 SCV000264231 pathogenic Noonan syndrome 2015-11-04 criteria provided, single submitter clinical testing
GenePathDx,Causeway Health Care Private Ltd RCV000487454 SCV000574532 pathogenic Noonan syndrome 4 2016-10-01 criteria provided, single submitter clinical testing Child with strong clinical suspicion of Noonan syndrome. Next generation DNA sequencing of peripheral blood sample has revealed the presence of a pathogenic variant NM_005633.3(SOS1):c.806T>C in the SOS1 gene in heterozygous state.
Invitae RCV000539275 SCV000659153 pathogenic Rasopathy 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 269 of the SOS1 protein (p.Met269Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a recurrent variant among individuals with Noonan syndrome, often observed as de novo events (PMID: 20683980, 19953625, 17586837, 21387466). ClinVar contains an entry for this variant (Variation ID: 40662). A different missense substitution at this codon (p.Met269Arg) has been determined to be pathogenic (PMID: 20683980, 17143282, 21387466). 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.
Ambry Genetics RCV000622587 SCV000742838 pathogenic Inborn genetic diseases 2017-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Integrated Genetics/Laboratory Corporation of America RCV000539275 SCV001363488 pathogenic Rasopathy 2019-11-18 criteria provided, single submitter clinical testing Variant summary: SOS1 c.806T>C (p.Met269Thr) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251358 control chromosomes (gnomAD). c.806T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome, often observed as a de novo variant (e.g. Baldassarre_2011, Denayer_2010, Longoni_2010, Koh_2019). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000157690 SCV000207674 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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