ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2183A>T (p.Lys728Ile) (rs397517156)

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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 RCV000038531 SCV000062209 pathogenic Noonan syndrome 2013-02-19 criteria provided, single submitter clinical testing The Lys728Ile variant in SOS1 has been reported in the literature in one patient with clinical features of Noonan Syndrome and the presence of embryonal rhabdom yosarcoma (Jongmans 2010). The variant was reported to have occurred de novo in this patient and this finding supports a pathogenic role. In addition, this var iant was identified to have occurred de novo in one proband with clinical featur es of Noonan syndrome by our laboratory. Computational analyses (biochemical ami no acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that t he Lys728Ile variant may impact the protein. In addition, this variant has not b een identified in large and broad populations by the NHLBI Exome Sequencing Proj ect (Lepri 2011, http://evs.gs.washington.edu/EVS/). In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM)
GeneDx RCV000159126 SCV000209070 pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing The K728I missense variant in the SOS1 gene has been reported previously in association with Noonan syndrome and an embryonal botryoid-type rhabdomyosarcoma and observed de novo (Jongmans et al., 2010; SCV000062209.4; Landrum et al. 2014). K728I was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K728I is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The conserved K728 residue within the RAS exchanger motif is predicted to form an autoinhibitory interaction with the Dbl-homology domain and stabilize inactive protein confirmation (Lepre et al., 2011).
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000495874 SCV000583559 likely pathogenic Noonan syndrome 4 2017-06-21 criteria provided, single submitter clinical testing
Invitae RCV001045366 SCV001209211 pathogenic Rasopathy 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 728 of the SOS1 protein (p.Lys728Ile). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of RASopathy disorders (PMID: 20461756, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40699). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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