ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1649T>C (p.Leu550Pro) (rs397517153)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159172 SCV000209117 pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing The L550P variant has been previously published in association with Noonan syndrome (Tartaglia et al. 2007). The L550P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). L550P 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, in vitro studies have shown that L550P increases ERK activation and RAS exchange rates compared to wild type (Smith et al., 2013). Missense variants in nearby residues (S548R, T549K, R552W/G/T/K/M/S) 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. Therefore, we interpret L550P as a pathogenic variant.
Invitae RCV000550001 SCV000659128 pathogenic Rasopathy 2017-07-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 550 of the SOS1 protein (p.Leu550Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 18854871, 22190897, 24451042), including co-segregation with disease in one family (PMID: 17143282). ClinVar contains an entry for this variant (Variation ID: 40680). Experimental studies, in vitro, have shown that this missense change results in increased RAS exchange rate and ERK activation compared to wild type (PMID: 23487764). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000550001 SCV001426865 pathogenic Rasopathy 2020-07-20 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1649T>C (p.Leu550Pro) results in a non-conservative amino acid change located in the plekstrin homology domain-RAS exchanger motif domain linker (Tartaglia_2007) 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 251176 control chromosomes (gnomAD). c.1649T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (Tartaglia_2007, Neumann_2008, Digilio_2011, Lepri_2014, Li_2019), including cosegregating with disease in families (Tartaglia_2007). These data indicate that the variant is very likely to be associated with disease. In vitro studies report this variant results in increased ERK activation and RAS exchange rate compared to wild type in cells. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038520 SCV000062198 pathogenic Noonan syndrome 2006-12-04 no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000159172 SCV002020779 pathogenic not provided 2019-02-22 no assertion criteria provided clinical testing

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