SOS1

protein-coding

SOS Ras/Rac guanine nucleotide exchange factor 1, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Gene summary

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]

Previous symbols:

GINGF

MANE transcript

NM_005633.4

Inheritance

ClinVar variants

P:90U:990B:599

Top phenotype

Noonan syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr2:38,962,206-39,124,345

External References & Databases

Ensembl (ENSG00000115904)

Transcript & Mutation Effects

hg38 • Region Span ~162.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012547

Submitter: Labcorp Genetics (formerly Invitae)

Noonan syndrome 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012547

Submitter: G2P

cardiofaciocutaneous syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015280

Submitter: ClinGen

There have been few patients presenting with a clinical suspicion of cardiofaciocutaneous syndrome (CFC) carrying a variant in SOS1 (Nystrom et al., 2008; Tumurkhuu et al., 2010). Variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of CFC versus other SOS1-RASopathies. The patients presented in these studies did not have convincing features described and/or there were not strong assertions made to diagnose these individuals with CFC. Therefore, the cases were not scored and the association has been classified as Disputed. Of note, SOS1 has also been classified as definitive in association with Noonan syndrome (NS) and as disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating SOS1 with either NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 6/1/18 (SOP Version 5).

fibromatosis, gingival, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007609

Submitter: Labcorp Genetics (formerly Invitae)

Costello syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0009026

Submitter: ClinGen

Only one case has been identified that had Costello syndrome-like features and a variant in the SOS1 gene (Tumurkhuu et al., 2010). This patient was described to have a phenotype between CS and cardiofaciocutaneous syndrome, that was more similar to CS, but the authors noted that there were no differentiating features to support diagnosis. Additionally, there is no further evidence to support the variant’s impact, so the association has been classified as Disputed. The HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, SOS1 has also been classified as definitive in association with Noonan syndrome (NS) and as disputed in association with CFC syndrome. The ClinGen RASopathy Gene Curation Expert Panel found no evidence associating SOS1 with either NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

Noonan syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012547

Submitter: Genomics England PanelApp

Noonan syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012547

Submitter: PanelApp Australia

Noonan syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There is a definitive association between alteration of the SOS1 gene and the Noonan syndrome (NS) phenotype. The maximum amount of scorable genetic evidence has been published showing that de novo and segregating variants occur in patients with NS (Lepri et al., 2011; Louati et al., 2014; Moncini et al., 2015; Narumi et al., 2007; Roberts et al., 2007; Tartaglia et al., 2007). The SOS1 gene is also located in the Ras/MAPK pathway which is associated with the NS phenotype(Aoki et al., 2016; Rauen, 2013). Of note, SOS1 has also been classified as disputed in association with cardiofaciocutaneous syndrome and Costello syndrome. The ClinGen RASopathy Gene Curation Expert Panel found no evidence associating SOS1 with either NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy GCEP on 7/24/18 (SOP Version 5).

Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

hereditary gingival fibromatosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016070

Submitter: Orphanet

Clinical Genomic Database (CGD)

Noonan syndrome 4AD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic

Intervention: Cardiovascular; Hematologic

Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis and hypertrophic cardiomyopathy) can be beneficial; The condition can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial

Refs: 11868160; 17143285; 17143282; 17586837; 18678287; 18925667; 19047498; 18456719; 19438935; 19077116; 20602484; 20876176; 20301303

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOS1 variants in ClinVar

34 Conditions Cataloged

RASopathyTotal: 1420

Cardiovascular phenotypeTotal: 712

not providedTotal: 574

Noonan syndrome 4Total: 373

not specifiedTotal: 297

Fibromatosis, gingival, 1Total: 285

Noonan syndromeTotal: 75

Noonan syndrome and Noonan-related syndromeTotal: 73

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005633.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	437 clinvar	16 clinvar	464
missense	24 clinvar	65 clinvar	937 clinvar	134 clinvar	10 clinvar	1170
nonsense			14 clinvar			14
start loss						0
frameshift		1 clinvar	21 clinvar	2 clinvar		24
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	24	66	990	573	26	1679

Highest pathogenic variant AF is 0.0000068216714

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005633.4	RefSeq	NP_005624.2	23	MANE Select
ENST00000402219.8	Ensembl	ENSP00000384675.2	23	MANE Select
NM_001382394.1	RefSeq	NP_001369323.1	23	Standard
NM_001382395.1	RefSeq	NP_001369324.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Non-small cell lung cancer - Homo sapiens (human)
Chronic myeloid leukemia - Homo sapiens (human)
Gastric cancer - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)

Biological Process

MAPK cascade
B cell homeostasis
hair follicle development
cardiac atrium morphogenesis
pericardium morphogenesis

Molecular Function

DNA binding
guanyl-nucleotide exchange factor activity
Ras guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
GTPase activator activity

Cellular Component

nucleosome
cytoplasm
cytosol
plasma membrane
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000426016
Coding exons: 23
Length: 142950
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125740
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.05	473	700	0.676	0.0000355	8767
Missense (PolyPhen)		118	285.7	0.41302		3583
Synonymous	0.0977	235	237	0.992	0.0000117	2523
Loss of Function	7.49	5	74.9	0.0667	0.00000487	840

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (By similarity). {ECO:0000250|UniProtKB:Q62245, ECO:0000269|PubMed:17339331, ECO:0000269|PubMed:8493579}.;
Disease: DISEASE: Fibromatosis, gingival, 1 (GINGF1) [MIM:135300]: A form of hereditary gingival fibromatosis, a rare condition characterized by a slow, progressive overgrowth of the gingiva. The excess gingival tissue can cover part of or the entire crown, and can result in diastemas, teeth displacement, or retention of primary or impacted teeth. GINGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common. {ECO:0000269|PubMed:11868160}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 4 (NS4) [MIM:610733]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. Some patients with NS4 have polyarticular villonodular synovitis. {ECO:0000269|PubMed:17143282, ECO:0000269|PubMed:17143285, ECO:0000269|PubMed:19020799, ECO:0000269|PubMed:19438935, ECO:0000269|PubMed:19953625, ECO:0000269|PubMed:20673819, ECO:0000269|PubMed:20683980, ECO:0000269|PubMed:21387466}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.384

Intolerance Scores

LoFtool: 0.0249
RVIS EVS: -1
RVIS percentile EVS: 8.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium