Noonan syndrome 7

Summary

Noonan syndrome 7 (MONDO:0013379) is a disease caused by BRAF (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: BRAF (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 148

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 7
Mondo ID	MONDO:0013379
OMIM	613706
DOID	DOID:0060585
NCIT	C176935
UMLS	C3150970
MedGen	462320
GARD	0015693
Is cancer (heuristic)	no

Also known as: BRAF Noonan syndrome · Noonan syndrome 7 · Noonan syndrome caused by mutation in BRAF · Noonan syndrome type 7 · NS7

Data availability: 148 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › Noonan syndrome 7

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, noonan syndrome 12, Noonan syndrome 13

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

148 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 22 conflicting classifications of pathogenicity, 16 benign/likely benign, 14 likely benign, 12 pathogenic, 9 pathogenic/likely pathogenic, 9 benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324583	NM_004333.6(BRAF):c.823G>A (p.Glu275Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13965	NM_004333.6(BRAF):c.736G>C (p.Ala246Pro)	BRAF	Pathogenic	reviewed by expert panel
13969	NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
13973	NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)	BRAF	Pathogenic	reviewed by expert panel
13974	NM_004333.6(BRAF):c.1406G>A (p.Gly469Glu)	BRAF	Pathogenic	reviewed by expert panel
13976	NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13979	NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)	BRAF	Pathogenic	reviewed by expert panel
13981	NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162795	NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162797	NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
177672	NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)	BRAF	Pathogenic	reviewed by expert panel
180784	NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)	BRAF	Pathogenic	reviewed by expert panel
222077	NM_004333.6(BRAF):c.1574T>C (p.Leu525Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29805	NM_004333.6(BRAF):c.722C>T (p.Thr241Met)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29806	NM_004333.6(BRAF):c.722C>G (p.Thr241Arg)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
29807	NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29808	NM_004333.6(BRAF):c.1593G>C (p.Trp531Cys)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
40347	NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
40390	NM_004333.6(BRAF):c.1802A>T (p.Lys601Ile)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
41446	NM_004333.6(BRAF):c.1801A>C (p.Lys601Gln)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
44811	NM_004333.6(BRAF):c.1743T>A (p.Asn581Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40370	NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser)	BRAF	Likely pathogenic	reviewed by expert panel
4819777	NM_004333.6(BRAF):c.1403T>G (p.Phe468Cys)	BRAF	Likely pathogenic	criteria provided, single submitter
4819911	NM_004333.6(BRAF):c.1387A>C (p.Ile463Leu)	BRAF	Likely pathogenic	criteria provided, single submitter
1050230	NM_004333.6(BRAF):c.1789C>T (p.Leu597=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1091347	NM_004333.6(BRAF):c.915G>A (p.Ala305=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1130636	NM_004333.6(BRAF):c.1797A>G (p.Thr599=)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318788	NM_004333.6(BRAF):c.52C>G (p.Leu18Val)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133720	NM_004333.6(BRAF):c.72G>C (p.Glu24Asp)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339665	NM_004333.6(BRAF):c.1690A>G (p.Met564Val)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BRAF	Definitive	Autosomal dominant	Noonan syndrome 7	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MRAS-complex mutants	1	2855.0×	0.004	BRAF
Signalling to p38 via RIT and RIN	1	2284.0×	0.004	BRAF
Negative feedback regulation of MAPK pathway	1	1903.3×	0.004	BRAF
ARMS-mediated activation	1	1631.4×	0.004	BRAF
Prolonged ERK activation events	1	1427.5×	0.004	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	1427.5×	0.004	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	1427.5×	0.004	BRAF
Signaling by FGFR3	1	1142.0×	0.004	BRAF
Signaling by FGFR4	1	1038.2×	0.004	BRAF
Frs2-mediated activation	1	951.7×	0.004	BRAF
Signaling by FGFR1	1	815.7×	0.004	BRAF
Spry regulation of FGF signaling	1	713.8×	0.005	BRAF
Signalling to ERKs	1	601.0×	0.005	BRAF
Negative regulation of FGFR3 signaling	1	439.2×	0.005	BRAF
Signaling by RAS mutants	1	423.0×	0.005	BRAF
Negative regulation of FGFR4 signaling	1	407.9×	0.005	BRAF
Signaling by FGFR2	1	407.9×	0.005	BRAF
Negative regulation of FGFR1 signaling	1	368.4×	0.005	BRAF
Negative regulation of FGFR2 signaling	1	368.4×	0.005	BRAF
Signaling by FGFR	1	346.1×	0.005	BRAF
RAF activation	1	335.9×	0.005	BRAF
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	BRAF
MAP2K and MAPK activation	1	285.5×	0.005	BRAF
Signaling by RAF1 mutants	1	278.5×	0.005	BRAF
Negative regulation of MAPK pathway	1	265.6×	0.005	BRAF
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	BRAF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	BRAF
Signaling downstream of RAS mutants	1	253.8×	0.005	BRAF
Oncogenic MAPK signaling	1	248.3×	0.005	BRAF
Signaling by NTRK1 (TRKA)	1	196.9×	0.007	BRAF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	5617.3×	0.003	BRAF
positive regulation of axon regeneration	1	3370.4×	0.003	BRAF
negative regulation of synaptic vesicle exocytosis	1	3370.4×	0.003	BRAF
CD4-positive, alpha-beta T cell differentiation	1	2808.7×	0.003	BRAF
myeloid progenitor cell differentiation	1	2407.4×	0.003	BRAF
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.003	BRAF
head morphogenesis	1	2106.5×	0.003	BRAF
establishment of protein localization to membrane	1	1872.4×	0.003	BRAF
negative regulation of fibroblast migration	1	1532.0×	0.003	BRAF
endothelial cell apoptotic process	1	1296.3×	0.003	BRAF
regulation of T cell differentiation	1	1203.7×	0.003	BRAF
face development	1	802.5×	0.003	BRAF
synaptic vesicle exocytosis	1	766.0×	0.003	BRAF
positive regulation of peptidyl-serine phosphorylation	1	766.0×	0.003	BRAF
stress fiber assembly	1	766.0×	0.003	BRAF
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.004	BRAF
positive regulation of axonogenesis	1	581.1×	0.004	BRAF
thyroid gland development	1	543.6×	0.004	BRAF
negative regulation of endothelial cell apoptotic process	1	495.6×	0.004	BRAF
T cell differentiation in thymus	1	411.0×	0.005	BRAF
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.005	BRAF
substrate adhesion-dependent cell spreading	1	343.9×	0.005	BRAF
thymus development	1	337.0×	0.005	BRAF
ERK1 and ERK2 cascade	1	318.0×	0.005	BRAF
positive regulation of stress fiber assembly	1	312.1×	0.005	BRAF
visual learning	1	306.4×	0.005	BRAF
long-term synaptic potentiation	1	280.9×	0.005	BRAF
epidermal growth factor receptor signaling pathway	1	247.8×	0.006	BRAF
somatic stem cell population maintenance	1	247.8×	0.006	BRAF
cellular response to xenobiotic stimulus	1	240.7×	0.006	BRAF

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BRAF	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BRAF	1,442

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRAF
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.