ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.797C>A (p.Thr266Lys) (rs137852812)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038570 SCV000062248 pathogenic Noonan syndrome 2012-06-26 criteria provided, single submitter clinical testing The Thr266Lys variant in SOS1 has been identified in the literature in several i ndividuals with clinical features of Noonan syndrome (Ko 2008, Ferrero 2008, Den ayer 2010, Pierpont 2009, Roberts 2007). This variant has been reported to have occurred de novo in at least one individual with sporadic disease (Denayer 2010) . In summary, this variant meets our criteria to be classified as pathogenic bas ed on it occurring de novo and its high frequency in individuals with features o f Noonan syndrome (http://www.pcpgm.partners.org/lmm).
GeneDx RCV000213007 SCV000209100 pathogenic not provided 2017-04-06 criteria provided, single submitter clinical testing The T266K variant has been published previously in association with Noonan syndrome, including apparently de novo occurrences (Denayer et al., 2010; Lepri et al., 2011; Croonen et al., 2013). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000062248.4; Landrum et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T266K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the DH domain that is conserved in mammals. Missense variants in a nearby residue (M269R/T) 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.
Invitae RCV000149833 SCV000553269 pathogenic Rasopathy 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 266 of the SOS1 protein (p.Thr266Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Noonan syndrome (PMID: 17143285, 23665959, 18678287, 22420426, 19077116, 21387466, 19020799, 19953625, 23885229).  ClinVar contains an entry for this variant (Variation ID: 12869) Experimental studies involving protein stability modeling have predicted that this variant will disrupt the inhibitory binding network of the distal RAS binding site, reducing the stability of the inactive conformation of SOS1 and allowing for a gain of enzyme activity (PMID: 21387466). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515403 SCV000611323 pathogenic Gingival fibromatosis 1; Noonan syndrome 4 2017-05-18 criteria provided, single submitter clinical testing
OMIM RCV000013729 SCV000033976 pathogenic Noonan syndrome 4 2008-11-01 no assertion criteria provided literature only
Baylor Miraca Genetics Laboratories, RCV000149833 SCV000196677 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000038570 SCV000206736 pathogenic Noonan syndrome 2011-12-12 no assertion criteria provided clinical testing

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