SMARCB1-related schwannomatosis

Summary

SMARCB1-related schwannomatosis (MONDO:0024517) is a disease caused by SMARCB1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: SMARCB1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 78

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	SMARCB1-related schwannomatosis
Mondo ID	MONDO:0024517
OMIM	162091
DOID	DOID:0070480
NCIT	C186703
UMLS	C4048809
MedGen	887689
GARD	0025408
Is cancer (heuristic)	no

Also known as: schwannomatosis 1 · schwannomatosis, somatic · SWNTS1

Data availability: 78 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › skin neoplasm › schwannomatosis › SMARCB1-related schwannomatosis

Related subtypes (3): neurofibromatosis, type III, mixed central and peripheral, LZTR1-related schwannomatosis, 22q-related schwannomatosis

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

78 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 17 conflicting classifications of pathogenicity, 15 benign/likely benign, 14 pathogenic, 5 benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2506549	GRCh37/hg19 22q11.22-11.23(chr22:22893189-24177119)	BCR	Pathogenic	criteria provided, single submitter
1319646	NM_000268.4(NF2):c.448-1G>A	NF2	Pathogenic	criteria provided, multiple submitters, no conflicts
3298	NC_000022.11:g.(29668447_29671826)(29681601?)del	NF2	Pathogenic	no assertion criteria provided
3299	NM_000268.4(NF2):c.125_126insG (p.Gly43fs)	NF2	Pathogenic	no assertion criteria provided
3300	NM_000268.4(NF2):c.205_211del (p.Lys69fs)	NF2	Pathogenic	no assertion criteria provided
635372	NM_000268.4(NF2):c.363+1G>A	NF2	Pathogenic	criteria provided, single submitter
1686218	NM_003073.5(SMARCB1):c.307_346del (p.Asn103fs)	SMARCB1	Pathogenic	criteria provided, single submitter
1686219	NM_003073.5(SMARCB1):c.747dup (p.Thr250fs)	SMARCB1	Pathogenic	criteria provided, single submitter
239481	NM_003073.5(SMARCB1):c.*82C>T	SMARCB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501798	NM_003073.5(SMARCB1):c.1118+2T>C	SMARCB1	Pathogenic	criteria provided, single submitter
30201	NM_003073.5(SMARCB1):c.1085AGA[2] (p.Lys364del)	SMARCB1	Pathogenic	criteria provided, multiple submitters, no conflicts
410706	NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu)	SMARCB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8026	NM_003073.5(SMARCB1):c.34C>T (p.Gln12Ter)	SMARCB1	Pathogenic	criteria provided, multiple submitters, no conflicts
8028	NM_003073.5(SMARCB1):c.203_216delinsTACC (p.His68fs)	SMARCB1	Pathogenic	no assertion criteria provided
8029	NM_003073.5(SMARCB1):c.233-2_237del	SMARCB1	Pathogenic	no assertion criteria provided
8030	NM_003073.5(SMARCB1):c.629-361_795+2103dup	SMARCB1	Pathogenic	no assertion criteria provided
2578438	NM_000268.4(NF2):c.1192_1193del (p.Leu398fs)	NF2	Likely pathogenic	criteria provided, single submitter
2664991	NM_000268.4(NF2):c.1340+1G>C	NF2	Likely pathogenic	criteria provided, single submitter
2664995	NM_003073.5(SMARCB1):c.10del (p.Met4fs)	SMARCB1	Likely pathogenic	criteria provided, single submitter
3288	NM_000268.4(NF2):c.285CTT[1] (p.Phe96del)	NF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341086	NM_000268.4(NF2):c.*359G>A	NF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
457904	NM_000268.4(NF2):c.1701C>G (p.Asp567Glu)	NF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
527695	NM_000268.4(NF2):c.1232G>A (p.Arg411His)	NF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
565467	NM_000268.4(NF2):c.1619A>G (p.Asn540Ser)	NF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569354	NM_000268.4(NF2):c.215T>C (p.Val72Ala)	NF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135257	NM_003073.5(SMARCB1):c.1A>G (p.Met1Val)	SMARCB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340912	NM_003073.5(SMARCB1):c.607G>A (p.Ala203Thr)	SMARCB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340913	NM_003073.5(SMARCB1):c.628+13C>T	SMARCB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340915	NM_003073.5(SMARCB1):c.987-4G>C	SMARCB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340918	NM_003073.5(SMARCB1):c.*17C>T	SMARCB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 19 · 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
SMARCB1	Definitive	Autosomal dominant	SMARCB1-related schwannomatosis	16
COQ6	Limited	Autosomal dominant	SMARCB1-related schwannomatosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCB1	Orphanet:1465	Coffin-Siris syndrome
SMARCB1	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCB1	Orphanet:2495	Meningioma
SMARCB1	Orphanet:263662	Familial multiple meningioma
SMARCB1	Orphanet:93921	Full schwannomatosis
SMARCB1	Orphanet:99966	Atypical teratoid rhabdoid tumor
COQ6	Orphanet:280406	Familial steroid-resistant nephrotic syndrome with sensorineural deafness
COQ6	Orphanet:93921	Full schwannomatosis
BCR	Orphanet:261330	Distal 22q11.2 microdeletion syndrome
BCR	Orphanet:521	Chronic myeloid leukemia
BCR	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
BCR	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
SMARCE1	Orphanet:1465	Coffin-Siris syndrome
SMARCE1	Orphanet:2495	Meningioma
SMARCE1	Orphanet:263662	Familial multiple meningioma
NF2	Orphanet:2495	Meningioma
NF2	Orphanet:634475	Mosaic NF2-related schwannomatosis
NF2	Orphanet:637	Full NF2-related schwannomatosis
NF2	Orphanet:93921	Full schwannomatosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCB1	HGNC:11103	ENSG00000099956	Q12824	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	gencc,clinvar
COQ6	HGNC:20233	ENSG00000119723	Q9Y2Z9	Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial	gencc
BCR	HGNC:1014	ENSG00000186716	P11274	Breakpoint cluster region protein	clinvar
SMARCE1	HGNC:11109	ENSG00000073584	Q969G3	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	clinvar
NF2	HGNC:7773	ENSG00000186575	P35240	Merlin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCB1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	Core component of the BAF (hSWI/SNF) complex.
COQ6	Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial	FAD-dependent monooxygenase required for two non-consecutive steps during ubiquinone biosynthesis.
BCR	Breakpoint cluster region protein	Protein with a unique structure having two opposing regulatory activities toward small GTP-binding proteins.
SMARCE1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
NF2	Merlin	Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.0

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
Scaffold/PPI	1	3.5×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCB1	Other/Unknown	no		SNF5, Sfh1/SNF5, INI1_DNA-bd
COQ6	Other/Unknown	no		UbQ_mOase_COQ6, FAD-bd, UbiH/COQ6
BCR	Scaffold/PPI	no		C2_dom, RhoGAP_dom, DH_dom
SMARCE1	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf
NF2	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, Moesin_tail_sf

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	2
ganglionic eminence	2
cortical plate	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
caudate nucleus	1
nucleus accumbens	1
putamen	1
calcaneal tendon	1
dorsal motor nucleus of vagus nerve	1
endometrium epithelium	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCB1	214	ubiquitous	marker	embryo, ganglionic eminence, cortical plate
COQ6	209	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
BCR	275	ubiquitous	marker	nucleus accumbens, caudate nucleus, putamen
SMARCE1	197	ubiquitous	marker	calcaneal tendon, embryo, ganglionic eminence
NF2	283	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCB1	5,083
NF2	3,208
COQ6	3,105
SMARCE1	2,977
BCR	1,858

Intra-cohort edges

A	B	Sources
SMARCB1	SMARCE1	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCB1	Q12824	17
SMARCE1	Q969G3	8
NF2	P35240	6
BCR	P11274	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COQ6	Q9Y2Z9	84.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the canonical BAF (cBAF) complex	2	253.8×	4e-04	SMARCB1, SMARCE1
Formation of the polybromo-BAF (pBAF) complex	2	253.8×	4e-04	SMARCB1, SMARCE1
Formation of the embryonic stem cell BAF (esBAF) complex	2	240.4×	4e-04	SMARCB1, SMARCE1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	2	182.7×	5e-04	SMARCB1, SMARCE1
Regulation of endogenous retroelements	2	147.3×	6e-04	SMARCB1, SMARCE1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	2	120.2×	8e-04	SMARCB1, SMARCE1
Regulation of MITF-M-dependent genes involved in pigmentation	2	106.2×	8e-04	SMARCB1, SMARCE1
MITF-M-dependent gene expression	2	72.5×	0.002	SMARCB1, SMARCE1
RMTs methylate histone arginines	2	58.6×	0.002	SMARCB1, SMARCE1
Transcriptional regulation by RUNX1	2	58.6×	0.002	SMARCB1, SMARCE1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	47.1×	0.003	SMARCB1, SMARCE1
MITF-M-regulated melanocyte development	2	45.7×	0.003	SMARCB1, SMARCE1
Chromatin organization	2	32.6×	0.005	SMARCB1, SMARCE1
Chromatin modifying enzymes	2	28.9×	0.005	SMARCB1, SMARCE1
Epigenetic regulation of gene expression	2	28.6×	0.005	SMARCB1, SMARCE1
FGFR1 mutant receptor activation	1	228.4×	0.012	BCR
Ubiquinol biosynthesis	1	175.7×	0.014	COQ6
Signaling by cytosolic FGFR1 fusion mutants	1	126.9×	0.018	BCR
Signaling by Rho GTPases	2	13.7×	0.018	BCR, NF2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	13.4×	0.018	BCR, NF2
RHO GTPases activate PAKs	1	108.8×	0.019	NF2
Signaling by FGFR in disease	1	84.6×	0.023	BCR
Signaling by FGFR1 in disease	1	58.6×	0.031	BCR
Fcgamma receptor (FCGR) dependent phagocytosis	1	55.7×	0.031	NF2
RNA Polymerase II Transcription	2	9.0×	0.031	SMARCB1, SMARCE1
Regulation of actin dynamics for phagocytic cup formation	1	36.8×	0.044	NF2
Gene expression (Transcription)	2	7.1×	0.045	SMARCB1, SMARCE1
RHOB GTPase cycle	1	30.9×	0.049	BCR
RHOC GTPase cycle	1	29.3×	0.050	BCR
RAC2 GTPase cycle	1	25.4×	0.054	BCR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of cell differentiation	3	160.5×	4e-05	SMARCB1, SMARCE1, NF2
nucleosome disassembly	2	321.0×	6e-04	SMARCB1, SMARCE1
regulation of G0 to G1 transition	2	269.6×	6e-04	SMARCB1, SMARCE1
regulation of nucleotide-excision repair	2	240.7×	6e-04	SMARCB1, SMARCE1
regulation of mitotic metaphase/anaphase transition	2	198.3×	7e-04	SMARCB1, SMARCE1
positive regulation of T cell differentiation	2	182.2×	7e-04	SMARCB1, SMARCE1
positive regulation of myoblast differentiation	2	146.5×	8e-04	SMARCB1, SMARCE1
positive regulation of stem cell population maintenance	2	137.6×	8e-04	SMARCB1, SMARCE1
positive regulation of double-strand break repair	2	137.6×	8e-04	SMARCB1, SMARCE1
regulation of G1/S transition of mitotic cell cycle	2	122.6×	9e-04	SMARCB1, SMARCE1
negative regulation of cellular extravasation	1	3370.4×	0.002	BCR
single stranded viral RNA replication via double stranded DNA intermediate	1	3370.4×	0.002	SMARCB1
negative regulation of respiratory burst	1	3370.4×	0.002	BCR
negative regulation of neutrophil degranulation	1	1685.2×	0.003	BCR
negative regulation of blood vessel remodeling	1	1685.2×	0.003	BCR
Schwann cell proliferation	1	1123.5×	0.004	NF2
regulation of gliogenesis	1	1123.5×	0.004	NF2
intracellular protein transmembrane transport	1	1123.5×	0.004	BCR
positive regulation of glucose mediated signaling pathway	1	1123.5×	0.004	SMARCB1
RNA polymerase I preinitiation complex assembly	1	674.1×	0.006	SMARCB1
neutrophil degranulation	1	674.1×	0.006	BCR
negative regulation of cell growth involved in contact inhibition	1	674.1×	0.006	NF2
regulation of organelle assembly	1	674.1×	0.006	NF2
actin cytoskeleton organization	2	31.6×	0.006	BCR, NF2
macrophage migration	1	561.7×	0.006	BCR
negative regulation of macrophage migration	1	561.7×	0.006	BCR
regulation of cell cycle	2	29.8×	0.006	BCR, NF2
chromatin remodeling	2	29.2×	0.006	SMARCB1, SMARCE1
negative regulation of Schwann cell proliferation	1	481.5×	0.006	NF2
regulation of hippo signaling	1	481.5×	0.006	NF2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
BCR	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BCR	64	4
SMARCB1	0	0
COQ6	0	0
SMARCE1	0	0
NF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	BCR
DASATINIB ANHYDROUS	4	BCR
IMATINIB MESYLATE	4	BCR
INFIGRATINIB	4	BCR
NILOTINIB	4	BCR
BOSUTINIB	4	BCR
ASCIMINIB	4	BCR
DASATINIB	4	BCR
TIRBANIBULIN	4	BCR
IMATINIB	4	BCR
FEDRATINIB	4	BCR
TIVOZANIB	4	BCR
LENVATINIB	4	BCR
AXITINIB	4	BCR
IBRUTINIB	4	BCR
REGORAFENIB	4	BCR
CABOZANTINIB	4	BCR
VANDETANIB	4	BCR
TOVORAFENIB	4	BCR
NINTEDANIB	4	BCR
ERLOTINIB	4	BCR
CRIZOTINIB	4	BCR
TANESPIMYCIN	3	BCR
RESVERATROL	3	BCR
FLUMATINIB	3	BCR
RADOTINIB	3	BCR
MASITINIB	3	BCR
SARACATINIB	3	BCR
CANERTINIB	3	BCR
TESEVATINIB	3	BCR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
BCR	486	Binding:478, Functional:6, Toxicity:2
SMARCB1	7	Binding:7
SMARCE1	7	Binding:7

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BCR	486

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
PONATINIB	4	BCR
DASATINIB ANHYDROUS	4	BCR
IMATINIB MESYLATE	4	BCR
INFIGRATINIB	4	BCR
NILOTINIB	4	BCR
BOSUTINIB	4	BCR
ASCIMINIB	4	BCR
DASATINIB	4	BCR
TIRBANIBULIN	4	BCR
IMATINIB	4	BCR
FEDRATINIB	4	BCR
TIVOZANIB	4	BCR
LENVATINIB	4	BCR
AXITINIB	4	BCR
IBRUTINIB	4	BCR
REGORAFENIB	4	BCR
CABOZANTINIB	4	BCR
VANDETANIB	4	BCR
TOVORAFENIB	4	BCR
NINTEDANIB	4	BCR
ERLOTINIB	4	BCR
CRIZOTINIB	4	BCR
TANESPIMYCIN	3	BCR
RESVERATROL	3	BCR
FLUMATINIB	3	BCR
RADOTINIB	3	BCR
MASITINIB	3	BCR
SARACATINIB	3	BCR
CANERTINIB	3	BCR
TESEVATINIB	3	BCR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BCR
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	4	SMARCB1, COQ6, SMARCE1, NF2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCB1	7	—
COQ6	0	—
SMARCE1	7	—
NF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.