3M syndrome 1

Summary

3M syndrome 1 (MONDO:0010117) is a disease caused by CUL7 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CUL7 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 227

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	3M syndrome 1
Mondo ID	MONDO:0010117
OMIM	273750
UMLS	C2678312
MedGen	395592
GARD	0015239
Is cancer (heuristic)	no

Also known as: 3-M syndrome 1 · 3-M syndrome caused by mutation in CUL7 · 3-M syndrome caused by mutation in Cul7 · 3M1 · CUL7 3-M syndrome · Cul7 3-M syndrome · three M syndrome 1 · three M syndrome type 1

Data availability: 227 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › 3-M syndrome › 3M syndrome 1

Related subtypes (2): 3M syndrome 2, 3M syndrome 3

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

227 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 38 conflicting classifications of pathogenicity, 38 likely pathogenic, 25 pathogenic, 24 benign, 9 pathogenic/likely pathogenic, 8 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
998015	NM_014780.5(CUL7):c.[2164C>T;4911dup]		Pathogenic	no assertion criteria provided
998018	NM_014780.5(CUL7):c.[3129G>A;4763T>C]		Pathogenic	no assertion criteria provided
1012246	NM_014780.5(CUL7):c.3129G>A (p.Trp1043Ter)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
1027385	NM_014780.5(CUL7):c.4770_4773del (p.Cys1590fs)	CUL7	Pathogenic	no assertion criteria provided
1264352	NM_014780.5(CUL7):c.2064-1G>A	CUL7	Pathogenic	no assertion criteria provided
127244	NM_014780.5(CUL7):c.2592T>G (p.Tyr864Ter)	CUL7	Pathogenic	no assertion criteria provided
1613	NM_014780.5(CUL7):c.4333C>T (p.Arg1445Ter)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
1614	NM_014780.5(CUL7):c.4391A>C (p.His1464Pro)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1615	NM_014780.5(CUL7):c.4451_4452del (p.Val1484fs)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
1618	NM_014780.5(CUL7):c.3379_3380del (p.Trp1127fs)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
1619	NM_014780.5(CUL7):c.1570-3C>A	CUL7	Pathogenic	no assertion criteria provided
1687448	NM_014780.5(CUL7):c.4297C>T (p.Gln1433Ter)	CUL7	Pathogenic	criteria provided, single submitter
1705498	NM_014780.5(CUL7):c.2150_2151insA (p.Asn719fs)	CUL7	Pathogenic	criteria provided, single submitter
191331	NM_014780.5(CUL7):c.263del (p.Val88fs)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194657	NM_014780.5(CUL7):c.3041T>G (p.Leu1014Arg)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195894	NM_014780.5(CUL7):c.4717C>T (p.Arg1573Ter)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
218361	NM_014780.5(CUL7):c.3173-1G>C	CUL7	Pathogenic	no assertion criteria provided
2734865	NM_014780.5(CUL7):c.3136del (p.Leu1046fs)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
282301	NM_014780.5(CUL7):c.2164C>T (p.Arg722Ter)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
288359	NM_014780.5(CUL7):c.4318C>T (p.Arg1440Ter)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236717	NM_014780.5(CUL7):c.2875dup (p.Thr959fs)	CUL7	Pathogenic	no assertion criteria provided
3367199	NM_014780.5(CUL7):c.920_929del (p.Leu307fs)	CUL7	Pathogenic	criteria provided, single submitter
3593624	NM_014780.5(CUL7):c.3924_3931del (p.Leu1308_Ser1309insTer)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775963	NM_014780.5(CUL7):c.727_732+18del	CUL7	Pathogenic	criteria provided, single submitter
3901932	NM_014780.5(CUL7):c.4186C>T (p.Arg1396Ter)	CUL7	Pathogenic	criteria provided, single submitter
450651	NM_014780.5(CUL7):c.2130_2131delinsTGCCTG (p.Cys711fs)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4539829	NM_014780.5(CUL7):c.4295-6_4313del	CUL7	Pathogenic	criteria provided, single submitter
497425	NM_014780.5(CUL7):c.1648C>T (p.Arg550Ter)	CUL7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800989	NM_014780.5(CUL7):c.1144C>T (p.Arg382Ter)	CUL7	Pathogenic	criteria provided, multiple submitters, no conflicts
802219	NM_014780.5(CUL7):c.652del (p.Arg218fs)	CUL7	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
CUL7	Definitive	Autosomal recessive	3M syndrome 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CUL7	Orphanet:2616	3M syndrome
OBSL1	Orphanet:2616	3M syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CUL7	HGNC:21024	ENSG00000044090	Q14999	Cullin-7	gencc,clinvar
OBSL1	HGNC:29092	ENSG00000124006	O75147	Obscurin-like protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CUL7	Cullin-7	Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
OBSL1	Obscurin-like protein 1	Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CUL7	Other/Unknown	no		APC_su10/DOC_dom, Galactose-bd-like_sf, Rib_uL2_dom2
OBSL1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
stromal cell of endometrium	1
left ovary	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CUL7	274	ubiquitous	marker	stromal cell of endometrium, pituitary gland, adenohypophysis
OBSL1	287	ubiquitous	marker	right testis, left testis, left ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL7	7,312
OBSL1	4,202

Intra-cohort edges

A	B	Sources
CUL7	OBSL1	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OBSL1	O75147	10
CUL7	Q14999	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neddylation	2	47.4×	0.001	CUL7, OBSL1
XBP1(S) activates chaperone genes	1	107.7×	0.014	CUL7
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.053	CUL7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 dendrite morphogenesis	2	887.0×	2e-05	CUL7, OBSL1
regulation of mitotic nuclear division	2	624.1×	2e-05	CUL7, OBSL1
Golgi organization	2	133.8×	3e-04	CUL7, OBSL1
microtubule cytoskeleton organization	2	121.2×	3e-04	CUL7, OBSL1
cardiac myofibril assembly	1	648.1×	0.005	OBSL1
protein localization to Golgi apparatus	1	401.2×	0.006	OBSL1
placenta development	1	221.7×	0.010	CUL7
negative regulation of insulin receptor signaling pathway	1	187.2×	0.010	CUL7
epithelial to mesenchymal transition	1	156.0×	0.011	CUL7
mitotic cytokinesis	1	129.6×	0.011	CUL7
vasculogenesis	1	127.7×	0.011	CUL7
cytoskeleton organization	1	66.3×	0.019	OBSL1
ubiquitin-dependent protein catabolic process	1	37.1×	0.031	CUL7
protein ubiquitination	1	20.7×	0.051	CUL7
proteolysis	1	17.1×	0.058	CUL7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CUL7	0	0
OBSL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	OBSL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CUL7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CUL7	0	—
OBSL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.