ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1297G>A (p.Glu433Lys) (rs397517147)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038513 SCV000062191 pathogenic Noonan syndrome 2011-02-08 criteria provided, single submitter clinical testing The Glu433Lys variant has been identified in the literature in several individua ls with clinical features of Noonan syndrome and one individual with Cardio-faci o-cutaneous syndrome (Ko 2008, Nystrom 2008, Tartaglia 2007, Denayer 2010). This variant has been reported to have occurred de novo in sporadic disease (Nystrom 2008, Denayer 2010). Therefore, it is highly likely that this variant is pathog enic.
GeneDx RCV000157692 SCV000209107 pathogenic not provided 2021-06-07 criteria provided, single submitter clinical testing Published functional studies demonstrate E433K increases the activation of RAS binding (Gureasko et al., 2010); 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: 17586837, 21387466, 19020799, 18772396, 19953625, 17143282, 20133692, 20648242, 21851854, 21784453, 23756559, 24458522, 22848035, 18854871, 18456719, 24803665, 32036363, 31130284, 29493581, 12628188, 27535533)
Invitae RCV000467110 SCV000553272 pathogenic Rasopathy 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 433 of the SOS1 protein (p.Glu433Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (rs397517147, ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 17143282, 19953625, 19020799) or cardio-facio-cutaneous syndrome (PMID: 18456719). In a few of these individuals, this variant was shown to arise de novo (PMID: 19953625, 18456719). ClinVar contains an entry for this variant (Variation ID: 40669). Experimental studies have shown that this missense change results in increased SOS1 activity in vitro (PMID: 20133692). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157692 SCV000207676 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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