rs397517164

Positions:

• chr2-39058696-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS3 PS2 PS4_Moderate PP2 PM2 PM6

This summary comes from the ClinGen Evidence Repository: The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2). The p.Glu108Lys variant has been identified in several independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2; PMID:17143282; 23487764). In vitro functional studies provide some evidence that the p.Glu108Lys variant may impact protein function (PS3; PMID:17143282, 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). 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, PS3, PM6, PS4_Moderate, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261739/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.80

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 15 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.322G>A	p.Glu108Lys	missense_variant	3/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.322G>A	p.Glu108Lys	missense_variant	3/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2013	The Glu108Lys variant in SOS1 has been reported in 6 individuals with clinical f eatures of Noonan syndrome and segregated with disease in 1 affected relative (T artaglia 2007, Lepri 2011, LMM unpublished data). This variant has not been iden tified in large population studies. Functional studies have shown that the Glu10 8Lys variant leads to increased activation of SOS1 protein (Gureasko 2010, Smith 2013, Saliba 2013, Findlay 2013). However, these in vitro assays may not accura tely represent biological function. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance. -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2). The p.Glu108Lys variant has been identified in several independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2; PMID: 17143282; 23487764). In vitro functional studies provide some evidence that the p.Glu108Lys variant may impact protein function (PS3; PMID: 17143282, 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). 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, PS3, PM6, PS4_Moderate, PM2, PP2. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 20133692, 20133694). 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 40649). This missense change has been observed in individuals with Noonan Syndrome (PMID: 17143282, 21387466). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 108 of the SOS1 protein (p.Glu108Lys). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2021	Variant summary: SOS1 c.322G>A (p.Glu108Lys) results in a conservative amino acid change located in the Histone H2A/H2B/H3 domain (IPR007125) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251142 control chromosomes. c.322G>A has been reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2007, Lepri_2011, Kauffman_2020). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of pERK (i.e., increased RAS/MAPK output) via increased membrane association (example, Smith_2013, Gureasko_2009). Two clinical diagnostic laboratories and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PS3+PS4_Moderate -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2017

The E108K pathogenic variant in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007; Lepri et al., 2011). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where amino acids with similar properties to Glutamic Acid are tolerated across species. However, the E108K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, functional studies demonstrate that the E108K variant, which is located in the histone fold domain of the encoded protein, disrupts protein activation and membrane assocation (Gureasko et al., 2010; Saliba et al., 2014). We interpret E108K as a pathogenic variant, consistent with global developmental delay, learning disability, pulmonic valve stenosis, pectus excavatum, hypertelorism, and easy bruising. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.016	D
MutationAssessor	Benign	1.4	L;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;.
Polyphen		0.39	B;B;.;.
Vest4		0.76
MutPred		0.83		Gain of MoRF binding (P = 0.0053);Gain of MoRF binding (P = 0.0053);Gain of MoRF binding (P = 0.0053);.;
MVP		0.95
MPC		0.87
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.47

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: rs397517164; hg19: chr2-39285837; COSMIC: COSV67677217;