2-39022774-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005633.4(SOS1):c.1654A>G(p.Arg552Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R552K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 3.66

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39022773-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40683.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 2-39022774-T-C is Pathogenic according to our data. Variant chr2-39022774-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12871.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39022774-T-C is described in Lovd as [Pathogenic]. Variant chr2-39022774-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1654A>G	p.Arg552Gly	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1654A>G	p.Arg552Gly	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250922 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461556 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 4 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PM1, PM2, PM5, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 01, 2017	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Dec 22, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 05, 2019	PS2, PS3, PS4, PM5_strong, PM1, PM2, PP1, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2021	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) -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 16, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 17, 2015	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. -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	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. -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Feb 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2023	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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.86		Loss of solvent accessibility (P = 0.0159);Loss of solvent accessibility (P = 0.0159);Loss of solvent accessibility (P = 0.0159);
MVP		0.97
MPC		1.7
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852814; hg19: chr2-39249915; COSMIC: COSV101216611; COSMIC: COSV101216611;