Silver-Russell syndrome 3

Summary

Silver-Russell syndrome 3 (MONDO:0014663) is a disease caused by IGF2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: IGF2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Silver-Russell syndrome 3
Mondo ID	MONDO:0014663
OMIM	616489
UMLS	C4225307
MedGen	894912
GARD	0018463
Is cancer (heuristic)	no

Also known as: GRDF · growth restriction, severe, with distinctive facies · SRS3

Data availability: 25 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Silver-Russell syndrome › Silver-Russell syndrome 3

Related subtypes (10): Russell-silver syndrome, X-linked, silver-Russell syndrome due to 7p11.2p13 microduplication, silver-Russell syndrome due to an imprinting defect of 11p15, silver-Russell syndrome due to 11p15 microduplication, silver-Russell syndrome due to maternal uniparental disomy of chromosome 11, silver-Russell syndrome due to maternal uniparental disomy of chromosome 7, Silver-Russell syndrome 5, Silver-Russell syndrome 1, silver-russell syndrome 2, silver-russell syndrome 4

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

25 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 likely pathogenic, 7 pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1709875	NM_000612.6(IGF2):c.-6-2A>T	IGF2	Pathogenic	criteria provided, single submitter
204491	NM_000612.6(IGF2):c.23C>A (p.Ser8Ter)	IGF2	Pathogenic	no assertion criteria provided
2682156	NM_000612.6(IGF2):c.-6-2A>G	IGF2	Pathogenic	criteria provided, single submitter
917500	NM_000612.6(IGF2):c.110_117delinsAGGTAA (p.Leu37fs)	IGF2	Pathogenic	no assertion criteria provided
917501	NM_000612.6(IGF2):c.101G>A (p.Gly34Asp)	IGF2	Pathogenic	criteria provided, single submitter
2499591	NM_000612.6(IGF2):c.243_244del (p.Glu81fs)	INS-IGF2	Pathogenic	criteria provided, single submitter
917502	NM_000612.6(IGF2):c.157+3A>C	INS-IGF2	Pathogenic	no assertion criteria provided
1679294	NM_000612.6(IGF2):c.59C>A (p.Ser20Ter)	IGF2	Likely pathogenic	criteria provided, single submitter
2442125	NM_000612.6(IGF2):c.106del (p.Glu36fs)	IGF2	Likely pathogenic	criteria provided, single submitter
2502356	NM_000612.6(IGF2):c.357G>A (p.Trp119Ter)	IGF2	Likely pathogenic	criteria provided, single submitter
3236772	NM_000612.6(IGF2):c.252T>G (p.Cys84Trp)	IGF2	Likely pathogenic	criteria provided, single submitter
4081460	NM_000612.6(IGF2):c.184_200del (p.Arg61_Arg62insTer)	IGF2	Likely pathogenic	criteria provided, single submitter
917503	NM_000612.6(IGF2):c.195del (p.Ile66fs)	IGF2	Likely pathogenic	criteria provided, single submitter
976061	NM_000612.6(IGF2):c.100G>T (p.Gly34Cys)	IGF2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2178673	NM_000612.6(IGF2):c.439G>C (p.Glu147Gln)	IGF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
710647	NM_001127598.3(IGF2):c.97C>T (p.Gln33Ter)	IGF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1328522	NM_000612.6(IGF2):c.199G>A (p.Val67Ile)	IGF2	Uncertain significance	criteria provided, single submitter
1359677	NM_000612.6(IGF2):c.466C>T (p.Arg156Cys)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2617071	NM_000612.6(IGF2):c.412C>T (p.Arg138Trp)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2989064	NM_000612.6(IGF2):c.5G>A (p.Gly2Glu)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376575	NM_000612.6(IGF2):c.1A>G (p.Met1Val)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3528037	NM_000612.6(IGF2):c.13A>G (p.Met5Val)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891375	NM_000612.6(IGF2):c.518C>A (p.Pro173Gln)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
504012	NM_000612.6(IGF2):c.472del (p.Pro157_Leu158insTer)	IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
976226	NM_000612.6(IGF2):c.27del (p.Met9fs)	IGF2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
IGF2	Definitive	Autosomal dominant	Silver-Russell syndrome 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGF2	Orphanet:2128	Isolated hemihyperplasia
IGF2	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15
IGF2	Orphanet:231140	Silver-Russell syndrome due to an imprinting defect of 11p15
IGF2	Orphanet:231144	Silver-Russell syndrome due to 11p15 microduplication
IGF2	Orphanet:397590	Silver-Russell syndrome due to a point mutation

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
IGF2	HGNC:5466	ENSG00000167244	P01344	Insulin-like growth factor 2	gencc,clinvar
INS-IGF2	HGNC:33527	ENSG00000129965	F8WCM5	Insulin, isoform 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGF2	Insulin-like growth factor 2	The insulin-like growth factors possess growth-promoting activity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGF2	Other/Unknown	no		IGF2_C, Insulin-like, IGF2
INS-IGF2	Other/Unknown	no		Insulin, Insulin-like, Insulin-like_sf

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)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
placenta	1
sural nerve	1
body of pancreas	1
islet of Langerhans	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGF2	135	ubiquitous	marker	adrenal tissue, placenta, sural nerve
INS-IGF2	20	broad	marker	islet of Langerhans, pancreas, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGF2	4,294
INS-IGF2	1,005

Intra-cohort edges

A	B	Sources
IGF2	INS-IGF2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGF2	P01344	16
INS-IGF2	F8WCM5	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
SHC-related events triggered by IGF1R	1	1142.0×	0.002	IGF2
IRS-related events triggered by IGF1R	1	1038.2×	0.002	IGF2
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	951.7×	0.002	IGF2
CHD6, CHD7, CHD8, CHD9 subfamily	1	148.3×	0.010	IGF2
Platelet degranulation	1	87.8×	0.012	IGF2
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	IGF2

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
positive regulation of skeletal muscle tissue growth	1	3370.4×	0.003	IGF2
embryonic placenta morphogenesis	1	3370.4×	0.003	IGF2
regulation of muscle cell differentiation	1	2106.5×	0.003	IGF2
exocrine pancreas development	1	1685.2×	0.003	IGF2
negative regulation of muscle cell differentiation	1	1685.2×	0.003	IGF2
positive regulation of organ growth	1	1404.3×	0.003	IGF2
positive regulation of glycogen biosynthetic process	1	991.3×	0.003	IGF2
striated muscle cell differentiation	1	991.3×	0.003	IGF2
genomic imprinting	1	991.3×	0.003	IGF2
positive regulation of insulin receptor signaling pathway	1	842.6×	0.003	IGF2
positive regulation of vascular endothelial cell proliferation	1	842.6×	0.003	IGF2
embryonic placenta development	1	766.0×	0.003	IGF2
positive regulation of activated T cell proliferation	1	674.1×	0.003	IGF2
positive regulation of mitotic nuclear division	1	543.6×	0.004	IGF2
positive regulation of multicellular organism growth	1	495.6×	0.004	IGF2
insulin-like growth factor receptor signaling pathway	1	495.6×	0.004	IGF2
positive regulation of cell division	1	337.0×	0.005	IGF2
glucose metabolic process	1	255.3×	0.006	IGF2
insulin receptor signaling pathway	1	221.7×	0.007	IGF2
animal organ morphogenesis	1	191.5×	0.007	IGF2
osteoblast differentiation	1	121.2×	0.011	IGF2
positive regulation of MAPK cascade	1	80.6×	0.016	IGF2
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.016	IGF2
in utero embryonic development	1	72.0×	0.016	IGF2
positive regulation of cell population proliferation	1	33.6×	0.033	IGF2
regulation of DNA-templated transcription	1	31.6×	0.034	IGF2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.059	IGF2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	IGF2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IGF2	0	0
INS-IGF2	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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	IGF2, INS-IGF2

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)
IGF2	0	—
INS-IGF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.