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

dbSNP: rs397517153

Total submissions: 10

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	2023-03-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40680). This missense change has been observed in individuals with Noonan syndrome (PMID: 17143282, 18854871, 22190897, 24451042). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 550 of the SOS1 protein (p.Leu550Pro).
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.
Revvity Omics, Revvity	RCV000159172	SCV002020779	pathogenic	not provided	2019-02-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467515	SCV002763390	pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002467515	SCV002767734	pathogenic	Noonan syndrome 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome (MIM#610733) (OMIM). Gain of function is established for the vast majority of missense variants however, loss of function has also been suggested for one missense variant due to the resulting unstable protein (PMID: 17143285). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. The variant is located in a cluster of pathogenic variants in the PH-REM linker domain (Decipher; PMID: 17143282). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 5 individuals with Noonan syndrome (ClinVar; PMIDs: 17143282, 18854871, 31560489, 31219622). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant cDNA constructs transfected into HEK293T cells demonstrated increased pERK induction in serum starved cells and increased RAS exchange activity compared to wild type cDNA constructs (PMID: 23487764). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000159172	SCV004033721	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SOS1: PS4, PM1, PM2, PM5, PP3, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003398589	SCV004120009	pathogenic	SOS1-related condition	2023-06-01	criteria provided, single submitter	clinical testing	The SOS1 c.1649T>C variant is predicted to result in the amino acid substitution p.Leu550Pro. This variant has been reported in an individual with Noonan Syndrome (Tartaglia et al. 2007. PubMed ID: 17143282; Chinton et al. 2019. PubMed ID: 31560489; Table S1 - Li et al. 2019. PubMed ID: 31219622). Functional studies demonstrated elevated levels of pERK and an increased rate of RAS nucleotide exchange, consistent with a gain-of-function mechanism (Smith et al. 2013. PubMed ID: 23487764). Additionally, different amino acid substitutions near this residue (p.Ser548Arg, p.Thr549Lys, p.Arg552Gly, p.Arg552Trp, p.Arg552Lys, p.Arg552Thr, p.Arg552Met, p.Arg552Ser) have been reported as pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/40680/). This variant is interpreted as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038520	SCV000062198	pathogenic	Noonan syndrome	2006-12-04	no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV003150937	SCV003840163	pathogenic	Noonan syndrome 1		no assertion criteria provided	research