chr2-39007168-C-T

Position:

• chr2-39007168-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.2536G>A (p.Glu846Lys) 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 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys 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). Furthermore, the variant is in a location that has been defined to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). 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/CA261734/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 7.78

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]

SOS1 (HGNC:):

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.2536G>A	p.Glu846Lys	missense_variant	16/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.2536G>A	p.Glu846Lys	missense_variant	16/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2015	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2022	Published functional studies demonstrate that this variant results in increased EGF-evoked ERK activation and sustained endogenous RAS activation (Roberts et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26918529, 23673306, 24803665, 22555271, 21387466, 21041952, 18854871, 19077116, 17586837, 18651097, 17143282, 28492532, 30055033, 30417923, 31263281, 32753483, 33042901, 34184824, 30732632, 33219052, 17143285) -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2012	The Glu846Lys variant in SOS1 has previously been identified in many individuals with clinical features of Noonan syndrome (Lepri 2011, Marco Tartaglia 2007, Ne umann 2009, Roberts 2007, Zenker 2007). This variant has shown segregation consi stent with pathogenicity in a familial case and to have occurred de novo in spor adic cases. In summary, this variant meets our criteria to be classified as path ogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.2536G>A (p.Glu846Lys) 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 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys 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). Furthermore, the variant is in a location that has been defined to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). 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. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 846 of the SOS1 protein (p.Glu846Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17143285, 17586837, 18651097, 18854871, 19077116, 21387466, 23673306). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40706). 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: 17143285, 21041952). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2018	Variant summary: SOS1 c.2536G>A (p.Glu846Lys) results in a conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277182 control chromosomes (gnomAD and publication). The variant, c.2536G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Zenker_2007, Tartaglia_2007, Lepri_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. Authors found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts (Chen_2010). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 09, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 4 (MIM#610733) (PMID: 17143285). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RasGEF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

SOS1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2023

The SOS1 c.2536G>A variant is predicted to result in the amino acid substitution p.Glu846Lys. This variant has previously been reported in individuals with Noonan syndrome and in at least one report to have arose de novo (see for example - Tartaglia et al 2007. PubMed ID: 17143282; Li et al. 2013. PubMed ID: 23673306; Hakami et al. 2016. PubMed ID: 26918529). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Roberts et al. 2007. PubMed ID: 17143285). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

The p.E846K pathogenic mutation (also known as c.2536G>A), located in coding exon 16 of the SOS1 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple individuals with a clinical diagnosis of Noonan syndrome (Tartaglia M, Nat. Genet. 2007 Jan; 39(1):75-9; Roberts AE, Nat. Genet. 2007 Jan; 39(1):70-4; Zenker M, J. Med. Genet. 2007 Oct; 44(10):651-6; Neumann TE, Eur. J. Hum. Genet. 2009 Apr; 17(4):420-5; Lepri F, Hum. Mutat. 2011 Jul; 32(7):760-72; Li K, J Cutan Med Surg 2013 May-Jun; 17(3):212-8). In addition, functional studies demonstrated that this alteration resulted in increased RAS-ERK activation (Roberts AE, Nat. Genet. 2007 Jan; 39(1):70-4). Based on the supporting evidence, p.E846K is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;N;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.44
Sift	Benign	0.088	T;T;T
Sift4G	Benign	0.077	T;T;T
Polyphen		0.24	B;B;.
Vest4		0.87
MutPred		0.80		Gain of ubiquitination at E846 (P = 0.0162);Gain of ubiquitination at E846 (P = 0.0162);Gain of ubiquitination at E846 (P = 0.0162);
MVP		0.89
MPC		1.5
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.40

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: rs397517159; hg19: chr2-39234309; COSMIC: COSV67673763;