2-39051202-A-G

Position:

• chr2-39051202-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PS2 PP2 PP3 PM1

This summary comes from the ClinGen Evidence Repository: The c.806T>C (p.Met269Thr) variant in SOS1 has been reported in the literature in at least 2 unconfirmed and 1 confirmed de novo occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837; 19953625, 20683980). It has also been reported as a confirmed de novo occurrence in a patient with clinical features of a RASoapthy (PMID:20683980). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3). 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). 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, PS2_VeryStrong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA235344/MONDO:0018997/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SOS1 ENST00000402219.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 9.20

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 10 ACMG points.

• PS2: 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.
• 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.806T>C	p.Met269Thr	missense_variant	6/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.806T>C	p.Met269Thr	missense_variant	6/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461376 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

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	GeneDx	Dec 28, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic; This variant is associated with the following publications: (PMID: 19953625, 31560489, 30417923, 20683980, 24803665, 19020799, 21387466, 26280111, 17586837, 29037749, 31589614, 33300679, 29493581, 17143282, 20648242, 12628188) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2021	- -
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	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2015	- -

Noonan syndrome 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GenePathDx, GenePath diagnostics	Oct 01, 2016	Child with strong clinical suspicion of Noonan syndrome. Next generation DNA sequencing of peripheral blood sample has revealed the presence of a pathogenic variant NM_005633.3(SOS1):c.806T>C in the SOS1 gene in heterozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 16, 2022	A heterozygous missense variation in exon 6 of the SOS1 gene (chr2:g.39051202A>C;) that result in the amino acid substitution of Arginine for Methionine at codon 269 (p.Met269Arg; ENST00000402219.8) was detected. thep.Met269Arg variant has not been reported in the 1000 genomes, gnomAD and our internal databases. the in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT AND Mutation Taster2. the reference codon is conserved across species. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040662). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19953625, 17586837, 20683980, PS2_VS). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.895>=0.6, 3CNET: 0.892>=0.75). A missense variant is a common mechanism . It 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. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012870,VCV000981559, PMID:17143282). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Noonan syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2015	The p.Met269Thr variant has been reported in >10 individuals with clinical featu res of Noonan syndrome (Ko 2008, Longoni 2010, Denayer 2010, Lepri 2011, Zenker 2007; LMM unpublished data). In three of these probands, the variant occurred de novo (Zenker 2007, Denayer 2010, Longoni 2010). It was absent from large popula tion studies. In summary, this variant meets our criteria to be classified as pa thogenic for Noonan syndrome in an autosomal dominant manner (http://www.partner s.org/personalizedmedicine/LMM) based upon absence from controls and de novo occ urrences. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 04, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.806T>C (p.Met269Thr) variant in SOS1 has been reported in the literature in at least 2 unconfirmed and 1 confirmed de novo occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837; 19953625, 20683980). It has also been reported as a confirmed de novo occurrence in a patient with clinical features of a RASoapthy (PMID: 20683980). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3). 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). 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, PS2_VeryStrong. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in SOS1 is predicted to replace methionine with threonine at codon 269, p.(Met269Thr). The methionine residue is highly conserved (99/99 vertebrates, UCSC), and is located in Dbl homology domain. Met269 is a critical residue and is defined as a mutational hotspot (PMID: 29493581). There is a moderate physicochemical difference between methionine and threonine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with a clinical diagnosis of Noonan syndrome, identified as a de novo occurrence with confirmed parental relationships in at least one individual and as a de novo occurrence with unconfirmed parental relationships in at least one individual (PMID: 17586837, 19020799, 1995362, 20683980, 21387466). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PS4, PM1, PM2_Supporting, PP3. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2019	Variant summary: SOS1 c.806T>C (p.Met269Thr) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of 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 251358 control chromosomes (gnomAD). c.806T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome, often observed as a de novo variant (e.g. Baldassarre_2011, Denayer_2010, Longoni_2010, Koh_2019). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite 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	Dec 05, 2023	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the SOS1 protein (p.Met269Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17586837, 19953625, 20683980, 21387466). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40662). 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 with a positive predictive value of 95%. This variant disrupts the p.Met269 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17143282, 20683980, 21387466). 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. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

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Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

The p.M269T pathogenic mutation (also known as c.806T>C), located in coding exon 6 of the SOS1 gene, results from a T to C substitution at nucleotide position 806. The methionine at codon 269 is replaced by threonine, an amino acid with similar properties. This mutation was identified in multiple individuals with Noonan syndrome, including several de novo occurrences (Zenker M et al. J Med Genet. 2007 Oct;44:651-6; Ko JM et al. J Hum Genet. 2008 Nov;53:999-1006; Denayer E et al. Genes Chromosomes Cancer. 2010 Mar;49:242-52; Longoni M et al. Am J Med Genet A. 2010 Sep;152A:2176-84; Lepri F et al. Hum Mutat. 2011 Jul;32:760-72). 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. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 25, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.0050	B;B;.
Vest4		0.97
MutPred		0.81		Gain of glycosylation at M269 (P = 0.0308);Gain of glycosylation at M269 (P = 0.0308);Gain of glycosylation at M269 (P = 0.0308);
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.83

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: rs137852813; hg19: chr2-39278343;