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

dbSNP: rs267607079

Total submissions: 12

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, http://gnomad.broadinstitute.org). 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, Mass General Brigham Personalized Medicine	RCV000038525	SCV000062203	pathogenic	Noonan syndrome	2008-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000213008	SCV000209123	pathogenic	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Different missense variants involving this residue (p.R552W, p.R552K, p.R552T, p.R552G, p.R552M) or neighboring residues (p.T549K , p.T549KA, p.L550P, p.D555E, p.V556I) have been reported in individuals with Noonan spectrum disorders in ClinVar, HGMD, and/or individuals tested at GeneDx; Missense variants in this gene are often considered pathogenic (HGMD); 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: 18651097, 22848035, 22488759, 28378436, 18854871, 17586837, 20648242, 29493581, 17143282, 21387466, 12628188, 30417923, 31219622, 31785789)
Fulgent Genetics, Fulgent Genetics	RCV000515298	SCV000611322	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000149832	SCV000659130	pathogenic	RASopathy	2024-11-11	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome and cardio-facio-cutaneous (CFC) syndrome (PMID: 17586837, 18651097, 18854871). ClinVar contains an entry for this variant (Variation ID: 40684). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. 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, 17143285, 17586837, 19352411, 20493809, 21387466, 23487764). 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.
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
3billion, Medical Genetics	RCV002250500	SCV002521345	pathogenic	Noonan syndrome 4	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 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: VCV000040684). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 17586837, 18854871) and reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 18854871). In addition, It has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 17586837). Different missense changes at the same codon (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012871, VCV000040681, VCV000040682, VCV000040683, VCV000372656). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002399362	SCV002707099	pathogenic	Cardiovascular phenotype	2016-05-04	criteria provided, single submitter	clinical testing	The p.R552S pathogenic mutation (also known as c.1656G>T), located in coding exon 10 of the SOS1 gene, results from a G to T substitution at nucleotide position 1656. The arginine at codon 552 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in sporadic and familial cases of Noonan syndrome (Zenker M, J. Med. Genet. 2007 Oct; 44(10):651-6; Neumann TE, Eur. J. Hum. Genet. 2009 Apr; 17(4):420-5) and a different nucleotide substitution (c.1656G>C), resulting in the same amino acid change, was confirmed de novo in affected individuals in another study (Tartaglia M, Nat. Genet. 2007 Jan; 39(1):75-9). In addition, substitutions of the R552 residue have been reported to account for one-third of SOS1 mutations in Noonan syndrome, with multiple mutations having been reported at this codon, including: p.552G, p.552K, p.552M, p.552T, and p.552W (Lepri F, Hum. Mutat. 2011 Jul; 32(7):760-72; Ezquieta B, Rev Esp Cardiol (Engl Ed) 2012 May; 65(5):447-55). Based on the supporting evidence, p.R552S is interpreted as a disease-causing mutation.
Institute of Human Genetics, University Hospital Muenster	RCV003128391	SCV003804905	pathogenic	See cases		criteria provided, single submitter	clinical testing	ACMG categories: PS2,PM1,PM2,PP3,PP5
Baylor Genetics	RCV000149832	SCV000196676	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines