Submissions for variant NM_005633.3(SOS1):c.1656G>C (p.Arg552Ser) (rs267607079)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156992	SCV000206715	pathogenic	Noonan syndrome	2012-06-08	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000159177	SCV000927898	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
ClinGen RASopathy Variant Curation Expert Panel	RCV000787998	SCV000927029	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-05-10	reviewed by expert panel	curation	The c.1656G>C (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). This variant has also been identified in at least 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Ser variant may impact protein function (PS3; PMID: 27304678). This residue has been identified as a hot spot. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Ser variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PM2, PS3, PM1_Strong, PP2, PP3.
Fulgent Genetics,Fulgent Genetics	RCV000763086	SCV000893612	pathogenic	Gingival fibromatosis 1; Noonan syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000159177	SCV000209122	pathogenic	not provided	2017-10-25	criteria provided, single submitter	clinical testing	The R552S variant has been published as a de novo pathogenic variant for Noonan syndrome and as a pathogenic variant for an allelic disorder, Noonan like/Multiple Giant Cell Lesion syndrome (Tartaglia et al., 2007; Beneteau et al., 2009; Neumann et al., 2009). The R552S variant is not observed in large population cohorts (Lek et al., 2016). The R552S variant 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 that is a recognized hot spot" for pathogenic variants within the SOS1 gene. Pathogenic missense variants in the same residue (R552G, R552T, R552K, R552M) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, this variant is pathogenic."
Invitae	RCV000654947	SCV000776855	pathogenic	Rasopathy	2018-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 552 of the SOS1 protein (p.Arg552Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 21387466, 24037001, 19020799, 22190897, 19352411, 23885229), including 2 affected individuals in which this variant was reported to be de novo (PMID: 17143282). ClinVar contains an entry for this variant (Variation ID: 12872). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different variant (c.1656G>T) giving rise to the same protein effect observed here (p.Arg552Ser) has been reported in several individuals affected with Noonan syndrome (PMID: 18854871, 18651097, 17586837).  It is estimated that substitutions at this codon account for 1/3 of all SOS1 mutations seen in individuals affected with Noonan syndrome (PMID: 21387466), which suggests that this codon is essential for proper SOS1 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000156992	SCV000062202	pathogenic	Noonan syndrome	2013-09-24	criteria provided, single submitter	clinical testing	The Arg552Ser variant in SOS1 has been identified in 7 individuals with either t he clinical features of Noonan syndrome or Noonan syndrome associated with multi ple giant-cell lesions, and occurred de novo in one of these individuals (Slezak 2010, Beneteau 2009, Tartaglia 2007, LMM unpublished data). This variant has al so not been identified in large population studies. In addition, multiple other variants affecting this position (Arg552Gly, Arg552Lys, Arg552Met, Arg552Thr) ha ve been reported in individuals with Noonan syndrome, and functional studies sho wed that another variant at the same position (Arg552Gly) caused increased and p rolonged RAS activation (Tartaglia 2007). In summary, the Arg552Ser variant meet s our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) ba sed on de novo occurrence, absence from controls, and supporting functional evid ence.
OMIM	RCV000013732	SCV000033979	pathogenic	Noonan syndrome 4	2008-11-15	no assertion criteria provided	literature only