ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1656G>T (p.Arg552Ser) (rs267607079)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000787997 SCV000927027 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.1656G>T (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in one patient and 2 other probands with clinical features of a RASopathy (PS2, PS4_Moderate; PMID 17586837, 18854871). Of note, one of these cases was an affected mother-child duo (PP1 not met; PMID: 17586837). This variant was absent from large population studies (PM2; gnomAD, This amino acid residue has been designated as a hotspot. 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). Of note, the p.Arg552Ser variant in SOS1 has also been a consequence of the c.1656G>C nucleotide change which has been classified as pathogenic (PS1; ClinVar ID 12872). 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, PS1, PM1_Strong, PM2, PS4_Moderate, PP2, PP3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038525 SCV000062203 pathogenic Noonan syndrome 2008-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000213008 SCV000209123 pathogenic not provided 2019-04-04 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18854871, 18651097, 22848035, 22488759, 28378436, 17586837, 30417923, 31219622)
Fulgent Genetics,Fulgent Genetics RCV000515298 SCV000611322 pathogenic Gingival fibromatosis 1; Noonan syndrome 4 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000149832 SCV000659130 pathogenic Rasopathy 2018-08-25 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 the literature in several individuals affected with Noonan syndrome (PMID: 17586837, 18854871) and cardio-facio-cutaneous (CFC) syndrome (PMID: 18651097). In addition, a different nucleotide substitution at the same position (c.1656G>C) giving rise to the same amino acid substitution (p.Arg552Ser) has been reported in multiple individuals affected with Noonan syndrome (PMID: 23885229, 22190897, 21387466, 19352411, 17143282, 19020799). ClinVar contains an entry for this variant (Variation ID: 40684). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Missense substitutions at this codon (p.Arg552Thr, Arg552Gly) have been determined to be pathogenic (PMID: 19352411, 21387466, 17143282, 17586837, 17143285, 21387466, 17143282, 23487764, 20493809, 17143285). This suggests that the arginine residue is critical for SOS1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000213008 SCV000884564 pathogenic not provided 2018-01-18 criteria provided, single submitter clinical testing The SOS1: c.1656G>T; p.Arg552Ser variant has been previously reported in association with Noonan syndrome (Zenker 2007, Neumann 2009) and is listed in ClinVar as pathogenic (Variation ID: 40684). Numerous variants of the arginine at codon 552 including p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, and p.Arg552Trp have all been associated with Noonan syndrome suggesting this amino acid is important for SOS1 protein function (Tartaglia 2007, Zenker 2007, Neumann 2009). Functional studies performed on the p.Arg552Gly variant indicate that it causes persistent ERK and RAS signaling activity upon ligand stimulation consistent with the established molecular mechanisms of the disease. (Tartaglia 2007). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on these observations the c.1656G>T; p.Arg552Ser variant has been classified pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000149832 SCV000918261 pathogenic Rasopathy 2017-12-30 criteria provided, single submitter clinical testing Variant summary: The SOS1 c.1656G>T (p.Arg552Ser) variant involves the alteration of a non conserved nucleotide. The variant is located within the helical linker between the PH and Rem domains (Sondermann_2005) and 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from control dataset of gnomAD (~245640 chrs tested), but was identified in several NS pts as a de novo event (Zenker_2007; Neumann_2009; Narumi_2008) and was shown to segregate in at least one familial case (Zenker_2007). Another alteration of the same nucleotide, c.1656G>C, leading to the identical alteration on the protein level, p.Arg552Ser, has been reported in multiple NS pts and is classified as Pathogenic. The codon Arg552 appears to be a mutational hot-spot, as other alteration, such as R552G, R552T, R552K, R552M have been reported in patients with NS. Taken together, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000213008 SCV001446614 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000149832 SCV000196676 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines

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