ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1654A>G (p.Arg552Gly) (rs137852814)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156980 SCV000206702 pathogenic Noonan syndrome 2011-10-20 no assertion criteria provided clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157693 SCV000884563 pathogenic not provided 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
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).
Center for Human Genetics, Inc RCV000013731 SCV000782296 pathogenic Noonan syndrome 4 2016-11-01 criteria provided, single submitter clinical testing
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
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.
Fulgent Genetics,Fulgent Genetics RCV000515160 SCV000611321 pathogenic Gingival fibromatosis 1; Noonan syndrome 4 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000157693 SCV000209119 pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The R552G variant in the SOS1 gene has been reported previously in association with both de novo and familial cases of Noonan syndrome (Tartaglia et al., 2007; Zenker et al., 2007; Cizmarova et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). R552G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (R552W/T/K/M/S) and nearby residues (S548R, T549K, L550P) have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. Functional studies demonstrate that this variant results in both prolonged RAS activation and increased basal levels of active RAS (Smith et al., 2013; Tartaglia et al., 2007). We interpret R552G as a pathogenic variant.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157693 SCV000207677 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000159174 SCV000253893 pathogenic Rasopathy 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 552 of the SOS1 protein (p.Arg552Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (rs137852814, ExAC no frequency). This variant has been reported as de novo in multiple sporadic cases of Noonan syndrome, and segregates with clinical features of Noonan syndrome in several families (PMID: 17143282, 17586837, 17143285, 21387466). ClinVar also contains entries for this variant (Variation ID: 12871). Experimental studies have shown that the Arg552Gly missense results in increased ERK and RAS activation in cell culture and zebrafish models (PMID: 17143282, 23487764, 20493809, 17143285). Multiple missense substitutions at this codon (p.Arg552Lys, p.Arg552Ser, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have been reported in individuals with Noonan syndrome (PMID: 17143282, 21387466, 19352411, 22465605), indicating that the Arg552 residue is important for normal SOS1 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.
OMIM RCV000013731 SCV000033978 pathogenic Noonan syndrome 4 2007-01-01 no assertion criteria provided literature only

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