SHOC2

Summary

SHOC2 (SHOC2 leucine rich repeat scaffold protein, HGNC:15454) is a protein-coding gene on chromosome 10q25.2, encoding Leucine-rich repeat protein SHOC-2 (Q9UQ13). Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway. It is a selective cancer dependency (DepMap: 17.4% of cell lines).

This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair.

Source: NCBI Gene 8036 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome-like disorder with loose anagen hair (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 708 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 80
• Cancer dependency (DepMap): dependent in 17.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_007373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15454
Approved symbol	SHOC2
Name	SHOC2 leucine rich repeat scaffold protein
Location	10q25.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0862, SOC2, SUR-8, SOC-2, SUR8
Ensembl gene	ENSG00000108061
Ensembl biotype	protein_coding
OMIM	602775
Entrez	8036

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000265277, ENST00000369452, ENST00000451838, ENST00000480155, ENST00000489390, ENST00000489783, ENST00000497305, ENST00000685059, ENST00000685613, ENST00000687592, ENST00000688928, ENST00000689118, ENST00000689300, ENST00000689997, ENST00000691151, ENST00000691369, ENST00000691441, ENST00000691843, ENST00000691903, ENST00000692776, ENST00000902509, ENST00000902510, ENST00000902511, ENST00000902512, ENST00000927906, ENST00000927907, ENST00000947765

RefSeq mRNA: 4 — MANE Select: NM_007373 NM_001269039, NM_001324336, NM_001324337, NM_007373

CCDS: CCDS58095, CCDS7568

Canonical transcript exons

ENST00000369452 — 9 exons

Exon	Start	End
ENSE00000724047	110985628	110985765
ENSE00000811848	110964125	110965061
ENSE00001868253	110919604	110919657
ENSE00001932452	111011610	111013665
ENSE00003481132	111009713	111009830
ENSE00003489085	111009248	111009385
ENSE00003539678	111007531	111007653
ENSE00003604378	111000415	111000545
ENSE00003627302	111004606	111004794

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 97.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5514 / max 299.3128, expressed in 1720 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107023	8.5592	1656
107022	2.7793	1345
107025	0.2129	84

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.58	gold quality
sural nerve	UBERON:0015488	95.91	gold quality
bone marrow	UBERON:0002371	95.23	gold quality
colonic epithelium	UBERON:0000397	95.16	gold quality
bone marrow cell	CL:0002092	94.91	gold quality
cauda epididymis	UBERON:0004360	94.84	gold quality
cortical plate	UBERON:0005343	94.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.62	gold quality
corpus epididymis	UBERON:0004359	94.30	gold quality
jejunal mucosa	UBERON:0000399	94.18	gold quality
islet of Langerhans	UBERON:0000006	94.17	gold quality
caput epididymis	UBERON:0004358	94.17	gold quality
tonsil	UBERON:0002372	93.92	gold quality
bone element	UBERON:0001474	93.91	gold quality
monocyte	CL:0000576	93.85	gold quality
mononuclear cell	CL:0000842	93.80	gold quality
tendon	UBERON:0000043	93.79	gold quality
leukocyte	CL:0000738	93.73	gold quality
colonic mucosa	UBERON:0000317	93.28	gold quality
seminal vesicle	UBERON:0000998	93.28	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.20	gold quality
dorsal root ganglion	UBERON:0000044	93.08	gold quality
periodontal ligament	UBERON:0008266	93.00	gold quality
cerebellar vermis	UBERON:0004720	92.97	gold quality
bronchial epithelial cell	CL:0002328	92.94	gold quality
upper leg skin	UBERON:0004262	92.92	gold quality
biceps brachii	UBERON:0001507	92.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.69	gold quality
medial globus pallidus	UBERON:0002477	92.41	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

181 targeting SHOC2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3065-5P	99.97	71.56	3281

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 17.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Erbin has a regulatory role in the Ras-Raf-MEK pathway and may inhibit ERK activation by disrupting the Sur-8-Ras/Raf interaction (PMID:16301319)
• Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. (PMID:19684605)
• Data suggest that Shoc2 regulates the spatio-temporal patterns of the Ras-ERK signaling pathway primarily by accelerating the Ras-Raf interaction. (PMID:20051520)
• Results indicate that the Shoc2 scaffold protein modulates Ras-dependent Raf1 activation in a Ca(2+)- and calmodulin-dependent manner. (PMID:20071468)
• no evidence of leukemogenic SHOC2 involvement in juvenile myelomonocytic leukemia (PMID:20110435)
• 92 patients with Noonan syndrome and related disorders to characterize mutations in the SHOC2 gene were analysed. (PMID:20882035)
• The p.Ser2Gly mutation demonstrated introduction of an N-myristoylation site, resulting in aberrant membrane targeting of SHOC2 and impaired translocation to the nucleus upon growth factor stimulation. (PMID:21548061)
• targeting of Shoc2 to late endosomes may facilitate EGFR-induced ERK activation under physiological conditions of cell stimulation by EGF, and therefore, may be involved in the spatiotemporal regulation of signaling through the RAS-RAF module (PMID:22606262)
• Noonan-like syndrome has been related to the invariant c.4A > G missense change in SHOC2. (PMID:22995099)
• SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor. (PMID:23076151)
• Both MRAS and SHOC2 play a key role in polarized migration. (PMID:24211266)
• A newborn heterozygous for the invariant c.4A>G missense change in SHOC2. (PMID:24458587)
• Data show that both Shoc2 and HUWE1 are necessary to control the levels and ubiquitination of the Shoc2 signaling partner, RAF-1. (PMID:25022756)
• Extreme phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation in Noonan-like syndrome with loose anagen hair. (PMID:25331583)
• ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of Epidermal Growth Factor, a stimulus that induces proliferation rather than differentiation in these cells. (PMID:25514808)
• Two unrelated Taiwanese patients have been described with Noonan-like syndrome with loose anagen hair who also have moyamoya disease and in whom heterozygous germline mutation in SHOC2 was found. (PMID:25858597)
• results demonstrate that PSMC5 is a new and important player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner. (PMID:26519477)
• Results provide evidence that SHOC2 trapping at different subcellular sites has a diverse impact on ERK signaling strength and dynamics, suggesting a dual counteracting modulatory role of SHOC2 in the control of ERK signaling exerted at different intracellular compartments. (PMID:27466182)
• Overexpression or knockdown of Sur8 increases or decreases, respectively, the proliferation or transformation of colorectal cancer (CRC) cell lines. Sur8 knockdown attenuates the migration and invasion of HCT116 CRC cells. (PMID:27469030)
• SHOC2 mutation is associated with Systemic lupus erythematosus. (PMID:29737035)
• we unraveled the anti-Colorectal cancer (CRC) function of Celastrol and confirmed for the first time that it inhibited the ERK1/2 pathway through binding to Shoc2 (PMID:30333251)
• miR-299-3p was significantly downregulated in thyroid cancer (TC) tissues and cell lines. miR-299-3p could inhibit cell proliferation and cell cycle progression, whereas remarkably promote cell apoptosis in TC cell lines. Bioinformatics predicted that SHOC2 might be a potential target of miR-299-3p. Subsequent Dual-Luciferase reporter analysis validated this hypothesis. (PMID:30657565)
• Study reports the identification of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy. This variant results in enhanced MRAS and PPP1CB binding and increased MAPK activation, but does not drive constitutive translocation of SHOC2 to the plasma membrane. (PMID:31059601)
• in fibroblasts from patients with inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) that harbor germline mutations in VCP, the levels of Shoc2 ubiquitination and ERK1/2 phosphorylation are imbalanced. (PMID:31091164)
• Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. (PMID:31108500)
• study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling (PMID:31213532)
• Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers. (PMID:31577942)
• Shoc2 single-domain antibodies can be used to understand functional mechanisms governing complex multiprotein signaling modules. (PMID:31869742)
• SHOC2 is associated with the survival of breast cancer cells and has prognostic value for patients with breast cancer. (PMID:31974612)
• The leucine-rich repeat signaling scaffolds Shoc2 and Erbin: cellular mechanism and role in disease. (PMID:32558243)
• Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome. (PMID:35348676)
• Structural basis for SHOC2 modulation of RAS signalling. (PMID:35768504)
• The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects. (PMID:35822684)
• Structure of the MRAS-SHOC2-PP1C phosphatase complex. (PMID:35830882)
• Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. (PMID:35831509)
• Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. (PMID:36175670)
• lncRNA MALAT1 regulates the resistance of breast cancer cells to paclitaxel via the miR-497-5p/SHOC2 axis. (PMID:36420706)
• LncRNA FALEC increases the proliferation, migration and drug resistance of cholangiocarcinoma through competitive regulation of miR-20a-5p/SHOC2 axis. (PMID:37166421)
• SHOC2 mediates the drug-resistance of triple-negative breast cancer cells to everolimus. (PMID:37170083)
• Aberrant N-myristoylation as a prelude to autoimmune manifestations in patients with SHOC2 mutations. (PMID:37793491)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	shoc2	ENSDARG00000040853
mus_musculus	Shoc2	ENSMUSG00000024976
rattus_norvegicus	Shoc2	ENSRNOG00000015339

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

Leucine-rich repeat protein SHOC-2 — Q9UQ13 (reviewed: Q9UQ13)

Alternative names: Protein soc-2 homolog, Protein sur-8 homolog

All UniProt accessions (5): Q9UQ13, A0A8I5KUD9, A0A8I5KUQ6, A0A8I5QJS4, X6RI37

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway. Acts as a scaffolding protein in the SMP complex. The SMP complex specifically dephosphorylates the inhibitory phosphorylation at ‘Ser-259’ of RAF1 kinase, ‘Ser-365’ of BRAF kinase and ‘Ser-214’ of ARAF kinase, stimulating their kinase activities. The SMP complex enhances the dephosphorylation activity and substrate specificity of PP1c.

Subunit / interactions. Component of the SHOC2-MRAS-PP1c (SMP) complex consisting of SHOC2, GTP-bound M-Ras/MRAS and the catalytic subunit of protein phosphatase 1 (either PPP1CA, PPP1CB or PPP1CC). SHOC2 and PP1c preferably bind M-Ras/MRAS, but they also bind K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS; these interactions are GTP-dependent and both SHOC2 and PP1c are required to form a stable complex. Interacts with PP1c in the absence of Ras GTPases. Interacts with M-Ras/MRAS and RAF1. Interacts with ERBIN; disrupts the interaction with RAF1 and Ras, preventing the activation of the Ras signaling pathway. Interacts with LZTR1.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Noonan syndrome-like disorder with loose anagen hair 1 (NSLH1) [MIM:607721] A syndrome characterized by Noonan dysmorphic features such as macrocephaly, high forehead, hypertelorism, palpebral ptosis, low-set and posteriorly rotated ears, short and webbed neck, pectus anomalies, in association with pluckable, sparse, thin and slow-growing hair. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains a N-terminal RVxF motif that is important for interaction with PP1c. PP1c (all isoforms) binds to the concave side of SHOC2, via LRR 2-5, 8-11, and 13-18. M-Ras/MRAS binds to the concave side of SHOC2, via LRR 1-10, 12 and 14-16.

Similarity. Belongs to the SHOC2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UQ13-1	1	yes
Q9UQ13-2	2

RefSeq proteins (4): NP_001255968, NP_001311265, NP_001311266, NP_031399* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family
IPR055414	LRR_R13L4/SHOC2-like	Domain

Pfam: PF13855, PF23598

UniProt features (94 total): strand 24, repeat 20, helix 20, mutagenesis site 17, turn 3, compositionally biased region 2, sequence variant 2, sequence conflict 2, chain 1, region of interest 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
7T7A	X-RAY DIFFRACTION	1.79
7TYG	X-RAY DIFFRACTION	1.9
7TXH	X-RAY DIFFRACTION	1.95
9BTN	X-RAY DIFFRACTION	2.04
7TVF	X-RAY DIFFRACTION	2.17
9BTP	X-RAY DIFFRACTION	2.37
7TVG	X-RAY DIFFRACTION	2.4
9OVJ	X-RAY DIFFRACTION	2.68
9BTM	X-RAY DIFFRACTION	2.73
7UPI	ELECTRON MICROSCOPY	2.89
7SD0	ELECTRON MICROSCOPY	2.95
9O65	ELECTRON MICROSCOPY	3
7SD1	X-RAY DIFFRACTION	3.19

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQ13-F1	88.00	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (17):

Position	Phenotype
64	impairs smp complex formation.
66	impairs smp complex formation.
109	impairs smp complex formation.
129	abolishes smp complex formation; when associated with a-131.
131	abolishes smp complex formation; when associated with a-129.
131	impairs smp complex formation.
134	impairs smp complex formation; when associated with e-180 and e-226.
155	impairs smp complex formation.
175	abolishes smp complex formation.
177	abolishes smp complex formation.
180	impairs smp complex formation; when associated with e-134 and e-226.
223	impairs smp complex formation.
226	impairs smp complex formation; when associated with e-134 and e-180.
269	promotes smp complex formation; when associated with y-270.
270	promotes smp complex formation; when associated with h-269.
457	impairs smp complex formation. impairs smp complex formation; when associated with k-503.
503	impairs smp complex formation; when associated with k-457.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-5673000	RAF activation
R-HSA-9726840	SHOC2 M1731 mutant abolishes MRAS complex function
R-HSA-9726842	Gain-of-function MRAS complexes activate RAF signaling
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802957	Oncogenic MAPK signaling
R-HSA-9660537	Signaling by MRAS-complex mutants

MSigDB gene sets: 439 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_RESPONSE_TO_NERVE_GROWTH_FACTOR, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_RESPONSE_TO_GROWTH_HORMONE

GO Biological Process (11): fibroblast growth factor receptor signaling pathway (GO:0008543), positive regulation of neuron projection development (GO:0010976), intracellular signal transduction (GO:0035556), nerve growth factor signaling pathway (GO:0038180), regulation of MAPK cascade (GO:0043408), negative regulation of neuron differentiation (GO:0045665), positive regulation of neuron differentiation (GO:0045666), positive regulation of Ras protein signal transduction (GO:0046579), cellular response to growth hormone stimulus (GO:0071378), cyclic-GMP-AMP transmembrane import across plasma membrane (GO:0140361), negative regulation of neural precursor cell proliferation (GO:2000178)

GO Molecular Function (4): protein phosphatase 1 binding (GO:0008157), protein phosphatase regulator activity (GO:0019888), protein phosphatase binding (GO:0019903), protein binding (GO:0005515)

GO Cellular Component (5): protein phosphatase type 1 complex (GO:0000164), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signaling by MRAS-complex mutants	2
RAF/MAP kinase cascade	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Oncogenic MAPK signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
neuron differentiation	2
regulation of neuron differentiation	2
protein phosphatase binding	2
cytoplasm	2
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
signal transduction	1
neurotrophin signaling pathway	1
cellular response to nerve growth factor stimulus	1
MAPK cascade	1
regulation of intracellular signal transduction	1
negative regulation of cell differentiation	1
positive regulation of cell differentiation	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
response to growth hormone	1
cellular response to peptide hormone stimulus	1
purine ribonucleotide transport	1
adenine nucleotide transport	1
cyclic nucleotide transport	1
import across plasma membrane	1
guanine nucleotide transmembrane transport	1
negative regulation of cell population proliferation	1
neural precursor cell proliferation	1
regulation of neural precursor cell proliferation	1
phosphoprotein phosphatase activity	1
phosphatase regulator activity	1
phosphatase binding	1
binding	1
protein serine/threonine phosphatase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHOC2	MRAS	O14807	984
SHOC2	PPP1CB	P37140	939
SHOC2	PPP1CC	P36873	919
SHOC2	SOS1	Q07889	858
SHOC2	NRAS	P01111	812
SHOC2	KSR1	Q8IVT5	779
SHOC2	KRAS	P01116	759
SHOC2	ERBIN	Q96RT1	750
SHOC2	BRAF	P15056	746
SHOC2	PTPN11	Q06124	745
SHOC2	HRAS	P01112	728
SHOC2	PKP1	Q13835	695
SHOC2	MAP2K2	P36507	685
SHOC2	LZTR1	Q8N653	661
SHOC2	MAP2K1	Q02750	642

IntAct

51 interactions, top by confidence:

A	B	Type	Score
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
ERBIN	SHOC2	psi-mi:“MI:0915”(physical association)	0.620
SHOC2	ERBIN	psi-mi:“MI:0915”(physical association)	0.620
SHOC2	HRAS	psi-mi:“MI:0915”(physical association)	0.560
SHOC2	HRAS	psi-mi:“MI:0914”(association)	0.560
ALDOB	ALDOA	psi-mi:“MI:0914”(association)	0.550
SHOC2	HMGN2	psi-mi:“MI:0915”(physical association)	0.400
SHOC2	H2BC12L	psi-mi:“MI:0915”(physical association)	0.400
SHOC2	H1-2	psi-mi:“MI:0915”(physical association)	0.400
Shoc2		psi-mi:“MI:0915”(physical association)	0.400
PPP1CA	MRAS	psi-mi:“MI:0915”(physical association)	0.400
PPP1CA	NRAS	psi-mi:“MI:0915”(physical association)	0.400
PPP1CA	HRAS	psi-mi:“MI:0915”(physical association)	0.400
PPP1CB	MRAS	psi-mi:“MI:0915”(physical association)	0.400
SHOC2	MRAS	psi-mi:“MI:0915”(physical association)	0.400
	MRAS	psi-mi:“MI:0915”(physical association)	0.400
SHOC2	KRAS	psi-mi:“MI:0915”(physical association)	0.400
SHOC2	NRAS	psi-mi:“MI:0915”(physical association)	0.400
	SHOC2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (108): SHOC2 (Affinity Capture-MS), SHOC2 (Affinity Capture-MS), SHOC2 (Affinity Capture-MS), SHOC2 (Affinity Capture-MS), PSMC5 (Two-hybrid), PSMC5 (Affinity Capture-Western), MRAS (Affinity Capture-Western), SHOC2 (Affinity Capture-Western), SHOC2 (Affinity Capture-Western), PSMC5 (Reconstituted Complex), HUWE1 (Affinity Capture-Western), RAF1 (Affinity Capture-Western), SHOC2 (Affinity Capture-Western), SHOC2 (Affinity Capture-MS), SHOC2 (Affinity Capture-MS)

ESM2 similar proteins: A6QLV3, A7SFP1, A8XWW4, B0W6M9, B3LWU3, B3P3E8, B4IBI9, B4JTV9, B4LXW1, B4N9T4, B4PU77, B4QVR7, B5DX45, B6CZ61, B9F655, O35125, O88520, Q1L8Y7, Q22875, Q32KP2, Q4R3P6, Q4V8I7, Q53EV4, Q5F4C4, Q5FVI3, Q5GIG6, Q5M8G4, Q5RAV5, Q5RFE9, Q5ZLN0, Q6AYI5, Q6DHL5, Q6GPJ5, Q6INV3, Q6P1C6, Q6UXM1, Q6ZVD8, Q7SXW3, Q7Z4L9, Q80VQ1

Diamond homologs: A6QLV3, A7SFP1, A8XWW4, B0W6M9, B3LWU3, B3P3E8, B4IBI9, B4JTV9, B4LXW1, B4N9T4, B4PU77, B4QVR7, B5DX45, O88520, Q1L8Y7, Q22875, Q5F4C4, Q5RAV5, Q6AYI5, Q8AVI4, Q9UQ13, Q9VEK6

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
SHOC2	“up-regulates activity”	PPP1CA	binding
MAPK1	“down-regulates quantity by destabilization”	SHOC2	phosphorylation
MAPK3	“down-regulates quantity by destabilization”	SHOC2	phosphorylation
SCF-FBW7	“down-regulates quantity by destabilization”	SHOC2	polyubiquitination
SHOC2	up-regulates	MRAS	binding
PRKCD	“down-regulates quantity by destabilization”	SHOC2	phosphorylation
PRKCA	“down-regulates quantity by destabilization”	SHOC2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF activation	6	74.6×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	5	30.2×	1e-04
MAPK cascade	6	27.0×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

708 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	342
Likely benign	282
Benign	35

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
181528	NM_007373.4(SHOC2):c.519G>A (p.Met173Ile)	Pathogenic
2850800	NM_007373.4(SHOC2):c.519G>C (p.Met173Ile)	Pathogenic
6821	NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)	Pathogenic
973849	NM_007373.4(SHOC2):c.807_808delinsTT (p.Gln269_His270delinsHisTyr)	Pathogenic
1339314	NM_007373.4(SHOC2):c.157G>A (p.Gly53Arg)	Likely pathogenic
1339463	NM_007373.4(SHOC2):c.520C>T (p.Leu174Phe)	Likely pathogenic

SpliceAI

2215 predictions. Top by Δscore:

Variant	Effect	Δscore
10:110937251:G:GT	donor_gain	1.0000
10:110937251:G:T	donor_gain	1.0000
10:110937252:A:T	donor_gain	1.0000
10:110942049:C:G	donor_gain	1.0000
10:110985761:TATAG:T	donor_loss	1.0000
10:110985762:ATAG:A	donor_loss	1.0000
10:110985763:TAGGT:T	donor_loss	1.0000
10:110985764:AGGT:A	donor_loss	1.0000
10:110985765:GG:G	donor_loss	1.0000
10:110985767:T:A	donor_loss	1.0000
10:111000543:GAG:G	donor_gain	1.0000
10:111004602:ACAG:A	acceptor_loss	1.0000
10:111004603:CA:C	acceptor_loss	1.0000
10:111004604:A:AC	acceptor_loss	1.0000
10:111004604:A:AG	acceptor_gain	1.0000
10:111004605:G:GG	acceptor_gain	1.0000
10:111004605:GA:G	acceptor_gain	1.0000
10:111004605:GAGT:G	acceptor_gain	1.0000
10:111004605:GAGTC:G	acceptor_gain	1.0000
10:111004778:G:GG	donor_gain	1.0000
10:111004794:GGT:G	donor_loss	1.0000
10:111007525:T:TA	acceptor_gain	1.0000
10:111007527:CCA:C	acceptor_loss	1.0000
10:111007528:CAG:C	acceptor_loss	1.0000
10:111007529:A:AT	acceptor_loss	1.0000
10:111007530:G:A	acceptor_loss	1.0000
10:111007627:G:GT	donor_gain	1.0000
10:111007650:TGAGG:T	donor_loss	1.0000
10:111007654:GTT:G	donor_loss	1.0000
10:111007655:T:G	donor_loss	1.0000

AlphaMissense

3807 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:110964741:T:C	L128P	1.000
10:110964757:C:A	N133K	1.000
10:110964757:C:G	N133K	1.000
10:110964810:T:C	L151P	1.000
10:110964816:T:C	L153P	1.000
10:110964824:A:C	N156H	1.000
10:110964824:A:G	N156D	1.000
10:110964824:A:T	N156Y	1.000
10:110964825:A:T	N156I	1.000
10:110964826:T:A	N156K	1.000
10:110964826:T:G	N156K	1.000
10:110964879:T:A	L174H	1.000
10:110964879:T:C	L174P	1.000
10:110964882:A:C	D175A	1.000
10:110964882:A:G	D175G	1.000
10:110964888:G:T	R177L	1.000
10:110964890:C:G	H178D	1.000
10:110964892:T:A	H178Q	1.000
10:110964892:T:G	H178Q	1.000
10:110964893:A:G	N179D	1.000
10:110964893:A:T	N179Y	1.000
10:110964894:A:T	N179I	1.000
10:110964895:T:A	N179K	1.000
10:110964895:T:G	N179K	1.000
10:110964939:T:A	L194H	1.000
10:110964948:T:A	L197H	1.000
10:110964948:T:C	L197P	1.000
10:110964954:T:C	L199P	1.000
10:110964959:T:A	F201I	1.000
10:110964959:T:C	F201L	1.000

dbSNP variants (sampled 300 via entrez): RS1000031066 (10:110997829 G>C,T), RS1000039736 (10:111004172 A>G), RS1000077192 (10:110984407 A>G), RS1000163945 (10:110964914 T>C,G), RS1000192179 (10:111009951 A>G,T), RS1000268658 (10:111003434 T>C), RS1000295021 (10:110927914 T>A), RS1000313249 (10:110957896 A>G), RS1000320295 (10:110926061 C>G), RS1000346143 (10:110971860 G>A), RS1000404166 (10:110932580 A>G), RS1000512310 (10:110923089 C>G), RS1000527403 (10:110963067 G>T), RS1000531666 (10:110950586 A>G), RS1000549938 (10:110959038 T>C)

Disease associations

OMIM: gene MIM:602775 | disease phenotypes: MIM:607721, MIM:609942, MIM:163950, MIM:236750, MIM:192600, MIM:169300, MIM:616362, MIM:263200

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome-like disorder with loose anagen hair	Definitive	Autosomal dominant
Noonan syndrome-like disorder with loose anagen hair 1	Definitive	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant
cardiofaciocutaneous syndrome	Disputed Evidence	Autosomal dominant
Noonan syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Noonan syndrome-like disorder with loose anagen hair	Definitive	AD
Noonan syndrome	Disputed	AD
Costello syndrome	Disputed	AD
cardiofaciocutaneous syndrome	Disputed	AD

Mondo (14): RASopathy (MONDO:0021060), Noonan syndrome-like disorder with loose anagen hair 1 (MONDO:0054637), Noonan syndrome 3 (MONDO:0012371), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), Noonan syndrome (MONDO:0018997), non-immune hydrops fetalis (MONDO:0009369), Noonan syndrome-like disorder with loose anagen hair (MONDO:0011899), familial hypertrophic cardiomyopathy (MONDO:0024573), pectus excavatum (MONDO:0008213), Houge-Janssens syndrome 2 (MONDO:0014605), polycystic kidney disease 4 (MONDO:0033004), intellectual disability (MONDO:0001071), Costello syndrome (MONDO:0009026), cardiofaciocutaneous syndrome (MONDO:0015280)

Orphanet (9): RASopathy (Orphanet:536391), Noonan syndrome-like disorder with loose anagen hair (Orphanet:2701), Noonan syndrome (Orphanet:648), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Non-immune hydrops fetalis (Orphanet:363999), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome (Orphanet:457284), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000081	Duplicated collecting system
HP:0000174	Abnormal palate morphology
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000670	Carious teeth
HP:0000752	Hyperactivity

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010142_18	Fish- and plant-related diet	3.000000e-10
GCST010142_84	Fish- and plant-related diet	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D005660	Funnel Chest	C05.116.099.386; C05.660.386; C16.131.621.386
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
C535579	Cardiofaciocutaneous syndrome (supp.)
C537846	Noonan like syndrome (supp.)
C537847	Noonan syndrome 3 (supp.)
C564342	Noonan-Like Syndrome With Loose Anagen Hair (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
asparanin A	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Clorgyline	increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Potassium Dichromate	decreases expression	1
Thimerosal	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	affects expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F1PM	HyCyte HEK293T KO-hSHOC2	Transformed cell line	Female

Clinical trials (associated diseases)

286 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01486953	PHASE4	UNKNOWN	Pulmonary Mechanics During Minimally Invasive Repair of Pectus Excavatum
NCT02056301	PHASE4	TERMINATED	A Comparison Trial Between PCA and Epidural Analgesia for Pectus Excavatum Repair
NCT02169297	PHASE4	COMPLETED	Sub-Paraspinal Block in Nuss Patients. A Pilot Project
NCT02721017	PHASE4	COMPLETED	Cryoanalgesia vs. Epidural in the Nuss Procedure
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02812511	Not specified	COMPLETED	Pathophysiology Analysis of Costello Syndrome on Cellular Models
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT00960128	Not specified	COMPLETED	Observational Prospective Study on Patients Treated With Norditropin®
NCT02486731	Not specified	COMPLETED	Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes
NCT03435627	Not specified	COMPLETED	Post Marketing Surveillance on Long-term Use With Norditropin® (Short Stature Due to Noonan Syndrome)
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT05202210	Not specified	RECRUITING	Constitution of a Biological Collection to Study the Pathophysiology in Noonan Syndrome