Submissions for variant NM_005633.4(SOS1):c.1654A>G (p.Arg552Gly)

dbSNP: rs137852814

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000156980	SCV000616386	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	The c.1654A>G (p.Arg552Gly) 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 was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID: 17143282). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg552Gly variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156980	SCV000062199	pathogenic	Noonan syndrome	2015-08-17	criteria provided, single submitter	clinical testing	The p.Arg552Gly variant in SOS1 has been reported in >25 individuals with clinic al features of Noonan syndrome, occurred de novo in at least 5 of these individu als, and segregated with disease in 5 affected relatives (Roberts 2007, Zenker 2 007, Tartaglia 2007, Neumann 2009, Brasil 2010, Denayer 2010, LMM unpublished da ta). It was absent from large population studies. In vitro functional studies pr ovide evidence that the p.Arg552Gly variant impacts protein function (Roberts 20 07, Tartaglia 2007, Smith 2013). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon de novo occurrence, segregation studies, absence from controls, and f unctional evidence.
GeneDx	RCV000157693	SCV000209119	pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; variant results in both prolonged RAS activation and increased basal levels of active RAS (Smith et al., 2013; Tartaglia et al., 2007); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); 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: 17586837, 21387466, 24803665, 26607044, 22465605, 17143285, 18854871, 21340158, 25073238, 23487764, 17143282, 19953625, 28957739, 20683980, 19352411, 20493809, 24522193, 28851938, 28991257, 30417923, 31219622, 31560489, 20648242, 12628188, 33300679, 32368696, 33683002)
Invitae	RCV000159174	SCV000253893	pathogenic	RASopathy	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 552 of the SOS1 protein (p.Arg552Gly). This variant is present in population databases (rs137852814, gnomAD 0.0009%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17143285, 17586837, 21387466). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12871). 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. Experimental studies have shown that this missense change affects SOS1 function (PMID: 17143282, 17143285, 20493809, 23487764). This variant disrupts the p.Arg552 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17143282, 19352411, 21387466, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000157693	SCV000511333	pathogenic	not provided	2016-12-06	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000013731	SCV000590889	pathogenic	Noonan syndrome 4	2017-05-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515160	SCV000611321	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2022-04-21	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000013731	SCV000678214	pathogenic	Noonan syndrome 4	2017-08-01	criteria provided, single submitter	clinical testing	SOS1 NM_005633.3 exon10 p.Arg552Gly (c.1654A>G): This variant has been well reported in the literature, identified in >10 individuals with a diagnosis or clinical features of Noonan syndrome, at least 5 of whom carried this variant de novo and segregating with disease in at least 1 family member. (Roberts 2007 PMID:17143285, Tartaglia 2007 PMID:17143282, Zenker 2007 PMID:17586837, Brasil 2010 PMID:21340158, Denayer 2010 PMID:19953625, Lepri 2011 PMID:21387466, Eyselbergs 2014 PMID:25073238). This variant has also been identified by our laboratory as de novo in 1 individual with clinical suspicion of a RASopathy. This variant is present in 1/111194 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137852814). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:12871). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, several other variants at this position have been associated with disease (p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) and functional studies have shown a deleterious effect of this variant, suggesting that this region has critical functional significance (Sondermann 2005 PMID:16267129, Roberts 2007 PMID:17143285, Tartaglia 2007 PMID:17143282, Smith 2013 PMID:23487764). In summary, this variant is classified as pathogenic based on the data above (presence in multiple probands, presence as a de novo, absence from controls and predicted functional impact to protein).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159174	SCV000698614	pathogenic	RASopathy	2016-02-22	criteria provided, single submitter	clinical testing	Variant summary: The SOS1 c.1654A>G variant affects a conserved nucleotide, resulting in amino acid change from Arg to Gly. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Functional studies of ERK and RAS activation suggest that R552G increases ERK and RAS activation, which is in agreement with the known mechanism of disease for SOS1 mutations in NS (a gain of function). This variant was not found in 121302 control chromosomes, however it has been cited in many NS patients in the literature. The variant is considered a known pathogenic mutation in the literature, and the most frequent SOS1 variant associated with NS. Additionally, multiple clinical diagnostic labs classify the variant as pathogenic. Taken together, this variant was classified as pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000013731	SCV000782296	pathogenic	Noonan syndrome 4	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156980	SCV000884563	pathogenic	Noonan syndrome	2018-04-16	criteria provided, single submitter	clinical testing	The SOS1 c.1654A>G; p.Arg552Gly variant (rs137852814, ClinVar variant ID 12871) is a well-established pathogenic variant, having been identified in at least 17 individuals diagnosed with Noonan syndrome without being reported in any unaffected relatives (Brasil 2010, Lepri 2011, Roberts 2007, Tafazoli 2018, Tartaglia 2007). This variant is thought to disrupt regulation of the protein, functional studies have repeatedly demonstrated that its expression causes increased RAS pathway signaling (Roberts 2007, Smith 2013, Tartaglia 2007), and several other variants affecting this amino acid have also been identified as pathogenic for Noonan syndrome (Lepri 2011). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.0004% (identified on 1 out of 245658 chromosomes), and the arginine at position 552 is highly conserved, considering 13 species. Based on the available evidence, the p.Arg552Gly variant is classified as pathogenic.
Blueprint Genetics	RCV000157693	SCV000927988	pathogenic	not provided	2018-10-12	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000157693	SCV001446919	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000157693	SCV001502290	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000157693	SCV001715447	pathogenic	not provided	2019-05-05	criteria provided, single submitter	clinical testing	PS2, PS3, PS4, PM5_strong, PM1, PM2, PP1, PP2, PP3
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000013731	SCV001976736	pathogenic	Noonan syndrome 4	2021-08-10	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP5
Revvity Omics, Revvity	RCV000157693	SCV002021900	pathogenic	not provided	2020-04-03	criteria provided, single submitter	clinical testing
DASA	RCV000013731	SCV002107111	pathogenic	Noonan syndrome 4	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 17143282; 17143285; 20493809) - PS3_moderate.The c.1654A>G;p.(Arg552Gly) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12871; PMID: 21340158; PMID:PMID: 17143282; PMID: 28957739; PMID: 21387466; PMID: 29402968; PMID: 24522193; PMID: 23487764; PMID: 22465605; PMID: 17586837; PMID: 18854871; PMID: 19953625) - PS4. This variant is not present in population databases (rs137852814- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID:372656) - PM5. Missense variant in SOS1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Ambry Genetics	RCV002399321	SCV002704204	pathogenic	Cardiovascular phenotype	2023-02-24	criteria provided, single submitter	clinical testing	The p.R552G pathogenic mutation (also known as c.1654A>G), located in coding exon 10 of the SOS1 gene, results from an A to G substitution at nucleotide position 1654. The arginine at codon 552 is replaced by glycine, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with Noonan syndrome, including sporadic, familial, and one de novo occurrence (Tartaglia M et al. Nat. Genet. 2007 Jan;39:75-9; Roberts AE et al. Nat. Genet. 2007 Jan;39:70-4; Zenker M et al. J. Med. Genet., 2007 Oct;44:651-6; Neumann TE et al. Eur. J. Hum. Genet. 2009 Apr;17:420-5; Denayer E et al. Genes Chromosomes Cancer. 2010 Mar;49:242-52). Functional studies demonstrated an increased basal level of active Ras and prolonged Ras activation after epithelial growth factor stimulation (Tartaglia M et al. Nat. Genet. 2007 Jan;39:75-9). Other variants affecting this codon (including p.R552T and p.R552S) have also been reported in association with Noonan syndrome (Beneteau C et al. Eur J Hum Genet. 2009 Oct;17:1216-21; Zenker M et al. J. Med. Genet. 2007 Oct; 44(10):651-6; Tartaglia M et al. Nat. Genet. 2007 Jan; 39(1):75-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
3billion	RCV000013731	SCV003841665	pathogenic	Noonan syndrome 4	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17143282). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012871). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17143282). Different missense changes at the same codon (p.Arg552Lys, p.Arg552Met, p.Arg552Ser, p.Arg552Thr, p.Arg552Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012872, VCV000040681, VCV000040682, VCV000040683, VCV000040684, VCV000372656). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV000013731	SCV003915613	pathogenic	Noonan syndrome 4	2021-12-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013731	SCV004041038	pathogenic	Noonan syndrome 4	2023-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000013731	SCV000033978	pathogenic	Noonan syndrome 4	2007-01-01	no assertion criteria provided	literature only
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157693	SCV000207677	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing