rs397517172

Positions:

• chr2-39056704-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM6 PP2 PP3 PM1 PS3

This summary comes from the ClinGen Evidence Repository: The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466). In vitro functional studies provide some evidence that the p.Lys170Glu variant may impact protein function (PS3; PMID 21784453, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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.Lys170Glu 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, PM6, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA235342/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense, splice_region
• Scores: Splicing: ADA: 0.4589
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 7.91

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 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.508A>G	p.Lys170Glu	missense_variant, splice_region_variant	4/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.508A>G	p.Lys170Glu	missense_variant, splice_region_variant	4/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Published functional studies demonstrate enhanced activity of the Ras-MAPK pathway (Smith et al., 2013; Lee et al., 2011); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21387466, 23487764, 19020799, 21784453, 24803665, 26918529, 34008892, 32333414, 35986401, 34643321, 35979676, 34163525, 29493581, 35770001, 35188046, 33677855) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Apr 05, 2022	PM1, PS3, PM6, PP3, PP2, PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Noonan syndrome 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.K170E in SOS1 (NM_005633.4) has been previously reported in multiple patients with Noonan syndrome. Functional studies depict a damaging effect (Smith MJ et al; Lee BH et al). The variant has been submitted to Clinvar as Pathogenic and has been reviewed by an expert Rasopathy curator panel. The p.K170E variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.K170E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The lysine residue at codon 170 of SOS1 is conserved in all mammalian species. The nucleotide c.508 in SOS1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Apr 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 07, 2022	ACMG classification criteria: PS3 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -

Noonan syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466). In vitro functional studies provide some evidence that the p.Lys170Glu variant may impact protein function (PS3; PMID 21784453, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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.Lys170Glu 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, PM6, PS3. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2011	The Lys170Glu has been reported in four individuals with clinical features of No onan syndrome (Ko 2008, Lee 2011, Lepri 2011). In addition, this variant has occ urred de novo in two individuals (Ko 2008, LMM unpublished data). Furthermore, functional data indicates that this variant leads to gain-of-function (Lee 2011) , which is an established pathogenic mechanism in Noonan syndrome. In summary, t his variant meets our criteria to be classified as pathogenic (http://pcpgm.part ners.org/LMM). -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2021	Variant summary: SOS1 c.508A>G (p.Lys170Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251282 control chromosomes. c.508A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions (e.g. Ko_2008, Denayer_2010, Lepri_2011, vanTrier_2015). These data indicate that the variant is very likely to be associated with disease. Two functional studies showed that this variant had a gain-of-function effect (Lee_2011, Smith_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 170 of the SOS1 protein (p.Lys170Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19020799, 19953625, 21387466). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40651). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SOS1 function (PMID: 21784453). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 25, 2018

The SOS1 c.508A>G; p.Lys170Glu variant (rs397517172), is reported in the literature in multiple individuals affected with Noonan syndrome (Denayer 2010, Ko 2008, Lepri 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40651), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein shows increased activation of Ras and ERK, due to structural changes in the autoinhibitory HF domain (Lee 2011, Smith 2013). The lysine at codon 170 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Lys170Glu variant is considered to be pathogenic. References: Denayer E et al. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer. 2010 Mar;49(3):242-52. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Lee BH et al. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011 Dec;159(6):1029-35. Lepri F et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011 Jul;32(7):760-72. Smith MJ et al. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9. -

Neonatal hypotonia Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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SOS1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2024

The SOS1 c.508A>G variant is predicted to result in the amino acid substitution p.Lys170Glu. This variant has been reported in at least six individuals with Noonan syndrome and has been reported as a likely de novo variant in at least two of these cases (Ko et al. 2008. PubMed ID: 19020799; Denayer et al. 2010. PubMed ID: 19953625; Lepri et al. 2011. PubMed ID: 21387466; Hakami et al. 2016. PubMed ID: 26918529). Additionally, functional studies demonstrate this variant results in increased RAS activation, p-ERK levels, and GDP-to-GTP exchange rate, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Lee et al. 2011. PubMed ID: 21784453; Smith et al. 2013. PubMed ID: 23487764). This variant has not been reported in a large population database, indicating this variant is rare and has been interpreted by multiple labs as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/40651/). Based on the available data, we classify the SOS1 c.508A>G (p.Lys170Glu) variant to be pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The p.K170E pathogenic mutation (also known as c.508A>G), located in coding exon 4 of the SOS1 gene, results from an A to G substitution at nucleotide position 508, which is located in the histine-like folds domain. The lysine at codon 170 is replaced by glutamic acid, an amino acid with some similar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of Noonan syndrome, including several cases described as de novo; clinical details were limited in some individuals (Ko JM et al. J. Hum. Genet., 2008 Dec;53:999-1006; Denayer E et al. Genes Chromosomes Cancer, 2010 Mar;49:242-52;; Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Shoji Y et al. Endocr J, 2019 Nov;66:983-994; Deden C et al. Prenat Diagn, 2020 07;40:972-983). Two in vitro functional studies have found this alteration results in significantly increased activation of the Ras pathway (Lee BH et al. J Pediatr. 2011;159(6):1029-35; Smith MJ et al. Proc Natl Acad Sci USA. 2013;110(12):4574-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.79
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.82		Loss of ubiquitination at K170 (P = 0.0199);Loss of ubiquitination at K170 (P = 0.0199);Loss of ubiquitination at K170 (P = 0.0199);
MVP		0.96
MPC		1.6
ClinPred		0.93	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.51
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: rs397517172; hg19: chr2-39283845;