rs137852813

Positions:

• chr2-39051202-A-C
• chr2-39051202-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000402219.8(SOS1):​c.806T>G​(p.Met269Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. M269T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOS1 ENST00000402219.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• 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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39051202-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40662.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 2-39051202-A-C is Pathogenic according to our data. Variant chr2-39051202-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 12870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39051202-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.806T>G	p.Met269Arg	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>G	p.Met269Arg	missense_variant	6/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461378 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727010

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Oct 25, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Nov 07, 2023	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2022	Published functional studies demonstrate that the p.(M269R) variant results in increased EGF-evoked ERK activation in comparison to wild-type (Roberts et al., 2007); 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: 25862627, 24803665, 26280111, 17586837, 23885229, 22420426, 17143282, 21387466, 29165300, 29074966, 18854871, 30417923, 20648242, 29493581, 12628188, 17143285) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2021	This variant occurred de novo in an individual tested at Athena Diagnostics with clinical features associated with this gene and in published literature (PMID: 29165300, 17143282, 30417923, 26280111, 22420426, 18854871, 19020799, 17586837, 23885229). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 17143285). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
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	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2020	Variant summary: SOS1 c.806T>G (p.Met269Arg) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251358 control chromosomes. c.806T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome (examples- Roberts_2007, Tartaglia_2007, Zenker_2007, Ko_2008, Neumann_2009,Lepri_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that the variant conveys a gain-of-function to the protein, as higher levels of RAS-GTP and ERK activation were observed in cells with the variant (example- Roberts_2007). Four other 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	Jun 09, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 19953625, 20683980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOS1 function (PMID: 17143285, 20683980). 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. ClinVar contains an entry for this variant (Variation ID: 12870). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17143285, 17586837, 19020799, 22420426, 23885229). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 269 of the SOS1 protein (p.Met269Arg). -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2013

The Met269Arg variant has been identified in several individuals with clinical f eatures of Noonan syndrome in the literature (Ko 2008, Tartaglia 2007, Roberts 2 007). This variant was determined to have occurred de novo in at least one of th ese individuals (Tartaglia 2007). In addition, this variant has been identified in seven individuals affected with the clinical features of Noonan syndrome by o ur laboratory (LMM unpublished data). This variant was also absent in large popu lation studies. In summary, the Met269Arg variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2018

The p.M269R pathogenic mutation (also known as c.806T>G), located in coding exon 6 of the SOS1 gene, results from a T to G substitution at nucleotide position 806. The methionine at codon 269 is replaced by arginine, an amino acid with similar properties. This mutation was identified in multiple individuals with Noonan syndrome, including at least 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; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Lepri F et al. Hum. Mutat., 2011 Jul;32:760-72; imek-Kiper PÖ et al. Clin. Genet., 2013 Feb;83:181-6; Croonen EA et al. Mol Syndromol, 2013 Jun;4:227-34). In addition, functional studies in cell lines demonstrate that this mutation significantly enhanced ERK activation and sustained RAS activation (Roberts AE et al. Nat. Genet., 2007 Jan;39:70-4; Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84). A disease-causing mutation, p.M269T, has been described in the same codon in multiple individuals with Noonan syndrome (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). 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	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.37	B;B;.
Vest4		0.98
MutPred		0.83		Gain of phosphorylation at T266 (P = 0.0797);Gain of phosphorylation at T266 (P = 0.0797);Gain of phosphorylation at T266 (P = 0.0797);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.93

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; COSMIC: COSV67674247;