rs137852813

Variant names:

• chr2-39051202-A-C
• rs137852813
• NM_005633.4:c.806T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

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

The NM_005633.4(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 NM_005633.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• 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 Lovd as [Pathogenic].
• 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 rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.806T>G	p.Met269Arg	missense_variant	Exon 6 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.806T>G	p.Met269Arg	missense_variant	Exon 6 of 23	1	NM_005633.4	ENSP00000384675.2

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Apr 14, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SOS1 c.806T>G; p.Met269Arg variant (rs137852813, ClinVar Variation ID: 12870) is reported in the literature in individuals with features of Noonan syndrome (Ko 2008, Roberts 2007, Tartaglia 2007), and described as de novo in at least one individual (Tartaglia 2007). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.931). A different variant at this codon (p.Met269Thr) has also been reported in individuals with Noonan syndrome (ClinVar Variation ID: 40662), further supporting the importance of this amino acid position. Based on available information, the p.Met269Arg variant is considered to be pathogenic. References: 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. PMID: 19020799. Roberts AE et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007 Jan;39(1):70-4. PMID: 17143285. Tartaglia M et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan;39(1):75-9. PMID: 17143282. -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome 4 Pathogenic:4

Oct 25, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 07, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:2

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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, 19020799, 22420426, 23885229). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12870). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SOS1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOS1 function (PMID: 17143285, 20683980). 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. For these reasons, this variant has been classified as Pathogenic. -

Aug 31, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Noonan syndrome 1 Pathogenic:1

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Pathogenic:1

Jul 17, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 03, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
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;