Submissions for variant NM_005633.4(SOS1):c.1656G>C (p.Arg552Ser)

dbSNP: rs267607079

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Laboratory for Molecular Medicine, Mass General Brigham 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giant-cell lesions, and occurred de novo in one of these individuals (Slezak 2010, Beneteau 2009, Tartaglia 2007, LMM unpublished data).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.
GeneDx	RCV000159177	SCV000209122	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21387466, 22848035, 29696744, 19352411, 24803665, 22190897, 22465605, 25862627, 19020799, 21784453, 30417923, 30050098, 29907801, 31560489, 34643321, 29493581, 20648242, 17143282, 12628188, 32668031, 18854871)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654947	SCV000776855	pathogenic	RASopathy	2022-06-10	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17586837, 18651097, 18854871, 19020799, 19352411, 21387466, 22190897, 23885229, 24037001). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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: 12872). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 552 of the SOS1 protein (p.Arg552Ser).
Fulgent Genetics, Fulgent Genetics	RCV000763086	SCV000893612	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000159177	SCV000927898	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000856746	SCV000999294	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000763086	SCV001190418	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2021-03-30	criteria provided, single submitter	clinical testing	SOS1 NM_005633.3 exon 10 p.Arg552Ser (c.1656G>C): This variant has been reported in the literature in several individuals with Noonan syndrome, including two cases reported to be de novo (Tartaglia 2007 PMID:17143282, Ko 2008 PMID:19020799, Beneteau 2009 PMID:19352411, Lepri 2011 PMID:21387466, Quaio 2013 PMID:24037001, Croonen 2013 PMID:23885229). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:12872). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Another variant (c.1656G>T) that gives rise to the same protein change (p.Arg552Ser) has also been reported in several individuals with Noonan syndrome (Zenker 2007 PMID:17586837, Narumi 2008 PMID:18651097, Neumann 2009 PMID:18854871). Additionally, several other variants at this amino acid position (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have also been reported in individuals with Noonan syndrome, supporting the potential functional relevance of this codon. In summary, this variant is classified as pathogenic based on the data above.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000654947	SCV001983605	pathogenic	RASopathy	2021-09-08	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.1656G>C (p.Arg552Ser) results in a non-conservative amino acid change in 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 250906 control chromosomes (gnomAD). p.Arg552Ser has been reported in the literature in multiple individuals affected with Noonan Syndrome, including at least two with confirmed de novo occurrence (e.g. Tartaglia_2007, Zenker_2007, Beneteau_2009, Lepri_2011, Croonen_2013). Several other missense variants at this amino acid residue (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have been reported in association with Noonan syndrome, indicating the functional importance of p.Arg552 residue, which has been defined as a hotspot for variation by the ClinGen RASopathy Variant Curation Expert Panel (PMID 29493581). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters, including the ClinGen RASopathy Variant Curation Expert Panel, (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000787998	SCV002060695	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000013732	SCV004806392	uncertain significance	Noonan syndrome 4	2024-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000013732	SCV000033979	pathogenic	Noonan syndrome 4	2008-11-15	no assertion criteria provided	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156992	SCV000206715	pathogenic	Noonan syndrome	2012-06-08	no assertion criteria provided	clinical testing