ClinVar Miner

Submissions for variant NM_005633.3(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 2018-11-19 criteria provided, single submitter clinical testing The E433K missense variant in the SOS1 gene has been observed de novo and reported in association with RASopathy spectrum disorders (Denayer et al., 2010; Nystrom et al., 2008; internal data). E433K is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution that occurs within the highly conserved pleckstrin homology domain (Tartaglia et al., 2007), and in vitro studies of E433K show it increases the activation of RAS binding (Gureasko et al., 2010).
Invitae RCV000467110 SCV000553272 pathogenic Rasopathy 2019-10-03 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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