ClinVar Miner

Submissions for variant NM_005633.4(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, In summary, this variant me ets our criteria to be classified as pathogenic (
GeneDx RCV000159126 SCV000209070 likely pathogenic not provided 2020-08-04 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 20461756, 21387466)
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 2019-12-25 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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