primary familial polycythemia due to EPO receptor mutation

Summary

primary familial polycythemia due to EPO receptor mutation (MONDO:0007572) is a disease caused by EPOR (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: EPOR (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 87
• Phenotypes (HPO): 15

Clinical features

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000421	Epistaxis	Very frequent (80-99%)
HP:0001901	Polycythemia	Very frequent (80-99%)
HP:0002094	Dyspnea	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0004936	Venous thrombosis	Very frequent (80-99%)
HP:0011902	Abnormal hemoglobin	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0001907	Thromboembolism	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0012735	Cough	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	primary familial polycythemia due to EPO receptor mutation
Mondo ID	MONDO:0007572
OMIM	133100
Orphanet	90042
DOID	DOID:0060652
ICD-11	962836252
SNOMED CT	17342003
UMLS	C4551637
MedGen	1641215
GARD	0009843
Is cancer (heuristic)	no

Also known as: congenital erythrocytosis due to erythropoietin receptor mutation · congenital polycythemia due to erythropoietin receptor mutation · ECYT1 · EPOR familial polycythemia · erythrocytosis autosomal dominant benign · erythrocytosis, familial, 1 · erythrocytosis, familial, type 1 · erythrocytosis, somatic · familial erythrocytosis · familial erythrocytosis type 1 · familial erythrocytosis, 1 · familial polycythemia caused by mutation in EPOR · PFCP · primary congenital erythrocytosis · primary familial and congenital polycythemia

Data availability: 87 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial polycythemia › primary familial polycythemia due to EPO receptor mutation

Related subtypes (7): acquired polycythemia vera, Chuvash polycythemia, erythrocytosis, familial, 3, erythrocytosis, familial, 4, erythrocytosis, familial, 5, erythrocytosis, familial, 6, erythrocytosis, familial, 7

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

87 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 18 benign, 12 conflicting classifications of pathogenicity, 9 benign/likely benign, 6 affects, 6 likely benign, 3 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16595	NM_000121.4(EPOR):c.1317G>A (p.Trp439Ter)	EPOR	Pathogenic	criteria provided, multiple submitters, no conflicts
14662	NM_004972.4(JAK2):c.1849G>T (p.Val617Phe)	INSL6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686181	NM_005475.3(SH2B3):c.1A>G (p.Met1Val)	SH2B3	Pathogenic	criteria provided, single submitter
268131	NM_000121.4(EPOR):c.1316G>A (p.Trp439Ter)	EPOR	Likely pathogenic	criteria provided, single submitter
3899248	NM_000121.4(EPOR):c.950G>A (p.Trp317Ter)	EPOR	Likely pathogenic	no assertion criteria provided
4819730	NM_000121.4(EPOR):c.1340del (p.Pro447fs)	EPOR	Likely pathogenic	criteria provided, single submitter
268129	NM_000121.4(EPOR):c.1310G>A (p.Arg437His)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328142	NM_000121.4(EPOR):c.1139C>T (p.Pro380Leu)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328153	NM_000121.4(EPOR):c.215T>C (p.Val72Ala)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3380582	NM_000121.4(EPOR):c.1505C>G (p.Pro502Arg)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3893126	NM_000121.4(EPOR):c.1439T>C (p.Leu480Ser)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713659	NM_000121.4(EPOR):c.296C>T (p.Ala99Val)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890739	NM_000121.4(EPOR):c.610G>C (p.Glu204Gln)	EPOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028834	NM_004972.4(JAK2):c.1641+6T>C	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134552	NM_004972.4(JAK2):c.2171T>C (p.Ile724Thr)	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2052244	NM_004972.4(JAK2):c.337C>G (p.Leu113Val)	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367131	NM_004972.4(JAK2):c.2762-10_2762-9del	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
619973	NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)	SH2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16596	NM_000121.4(EPOR):c.1288dup (p.Asp430fs)	EPOR	Affects	no assertion criteria provided
16597	NM_000121.4(EPOR):c.1281dup (p.Ile428fs)	EPOR	Affects	no assertion criteria provided
16599	NM_000121.4(EPOR):c.1299_1305del (p.Gln434fs)	EPOR	Affects	no assertion criteria provided
16600	NM_000121.4(EPOR):c.1278C>G (p.Tyr426Ter)	EPOR	Affects	no assertion criteria provided
16601	NM_000121.4(EPOR):c.1283_1289dup (p.Ser432fs)	EPOR	Affects	no assertion criteria provided
2627536	NM_000121.4(EPOR):c.1362C>G (p.Tyr454Ter)	EPOR	Uncertain significance	criteria provided, single submitter
2920904	NM_000121.4(EPOR):c.499C>T (p.Leu167Phe)	EPOR	Uncertain significance	criteria provided, single submitter
328132	NM_000121.4(EPOR):c.*619C>T	EPOR	Uncertain significance	criteria provided, single submitter
328146	NM_000121.4(EPOR):c.980C>T (p.Pro327Leu)	EPOR	Uncertain significance	criteria provided, multiple submitters, no conflicts
328147	NM_000121.4(EPOR):c.864C>T (p.Ser288=)	EPOR	Uncertain significance	criteria provided, single submitter
328149	NM_000121.4(EPOR):c.596T>C (p.Leu199Pro)	EPOR	Uncertain significance	criteria provided, single submitter
328158	NM_000121.4(EPOR):c.-8G>T	EPOR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 9 · 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
EPOR	Strong	Autosomal dominant	primary familial polycythemia due to EPO receptor mutation	4
SH2B3	No Known Disease Relationship	Unknown	primary familial polycythemia due to EPO receptor mutation	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
EPOR	Orphanet:90042	Primary familial polycythemia
JAK2	Orphanet:131	Budd-Chiari syndrome
JAK2	Orphanet:3318	Essential thrombocythemia
JAK2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
JAK2	Orphanet:71493	Familial thrombocytosis
JAK2	Orphanet:729	Polycythemia vera
JAK2	Orphanet:824	Primary myelofibrosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gencc,clinvar
EPOR	HGNC:3416	ENSG00000187266	P19235	Erythropoietin receptor	gencc,clinvar
INSL6	HGNC:6089	ENSG00000120210	Q9Y581	Insulin-like peptide INSL6	clinvar
JAK2	HGNC:6192	ENSG00000096968	O60674	Tyrosine-protein kinase JAK2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
EPOR	Erythropoietin receptor	Receptor for erythropoietin, which mediates erythropoietin-induced erythroblast proliferation and differentiation.
INSL6	Insulin-like peptide INSL6	May have a role in sperm development and fertilization.
JAK2	Tyrosine-protein kinase JAK2	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications.

Protein-family classification

Druggable: 2 · Difficult: 1 · 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	7.3×	0.273
Kinase	1	6.9×	0.273
Scaffold/PPI	1	4.3×	0.283
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
EPOR	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Erythropoietin_rcpt
INSL6	Other/Unknown	no		Insulin-like, Insulin-like_pep_6, Insulin_CS
JAK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
leukocyte	1
mononuclear cell	1
left lobe of thyroid gland	1
olfactory bulb	1
type B pancreatic cell	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
blood vessel layer	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
EPOR	268	ubiquitous	marker	type B pancreatic cell, olfactory bulb, left lobe of thyroid gland
INSL6	152	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
JAK2	272	ubiquitous	marker	calcaneal tendon, monocyte, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAK2	6,197
SH2B3	1,617
EPOR	1,563
INSL6	509

Intra-cohort edges

A	B	Sources
EPOR	JAK2	biogrid_interaction, string_interaction
JAK2	SH2B3	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK2	O60674	164
EPOR	P19235	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH2B3	Q9UQQ2	63.45
INSL6	Q9Y581	54.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Erythropoietin activates Phospholipase C gamma (PLCG)	2	1087.6×	3e-05	EPOR, JAK2
Erythropoietin activates STAT5	2	1087.6×	3e-05	EPOR, JAK2
Signaling by Erythropoietin	2	692.1×	5e-05	EPOR, JAK2
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	2	634.4×	5e-05	EPOR, JAK2
Erythropoietin activates RAS	2	507.6×	7e-05	EPOR, JAK2
Signaling by SCF-KIT	2	165.5×	5e-04	SH2B3, JAK2
Factors involved in megakaryocyte development and platelet production	2	44.3×	0.007	SH2B3, JAK2
Signaling by Receptor Tyrosine Kinases	2	34.5×	0.010	SH2B3, JAK2
Interleukin-6 family signaling	1	475.8×	0.011	JAK2
IFNG signaling activates MAPKs	1	475.8×	0.011	JAK2
Interleukin-23 signaling	1	423.0×	0.011	JAK2
MAPK1 (ERK2) activation	1	380.7×	0.011	JAK2
Signaling by KIT in disease	1	380.7×	0.011	JAK2
MAPK3 (ERK1) activation	1	346.1×	0.011	JAK2
Signaling by Leptin	1	346.1×	0.011	JAK2
Interleukin-27 signaling	1	346.1×	0.011	JAK2
Interleukin-6 signaling	1	317.2×	0.011	JAK2
Interleukin-35 Signalling	1	317.2×	0.011	JAK2
Cytokine Signaling in Immune system	2	27.2×	0.011	SH2B3, JAK2
Hemostasis	2	24.0×	0.011	SH2B3, JAK2
Regulation of IFNG signaling	1	271.9×	0.012	JAK2
Prolactin receptor signaling	1	253.8×	0.012	JAK2
Negative regulation of FLT3	1	237.9×	0.013	SH2B3
RAF-independent MAPK1/3 activation	1	211.5×	0.013	JAK2
Interleukin-2 family signaling	1	211.5×	0.013	JAK2
IL-6-type cytokine receptor ligand interactions	1	211.5×	0.013	JAK2
Regulation of KIT signaling	1	200.3×	0.013	SH2B3
Signaling by CSF3 (G-CSF)	1	190.3×	0.013	JAK2
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	173.0×	0.014	JAK2
Interleukin-12 family signaling	1	158.6×	0.014	JAK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to interleukin-3	2	1872.4×	2e-05	SH2B3, JAK2
erythropoietin-mediated signaling pathway	2	1872.4×	2e-05	EPOR, JAK2
thrombopoietin-mediated signaling pathway	2	1404.3×	2e-05	SH2B3, JAK2
nuclear receptor-mediated mineralocorticoid signaling pathway	1	5617.3×	0.003	JAK2
symbiont-induced defense-related programmed cell death	1	5617.3×	0.003	JAK2
interleukin-35-mediated signaling pathway	1	5617.3×	0.003	JAK2
response to interleukin-12	1	2808.7×	0.004	JAK2
negative regulation of Kit signaling pathway	1	2808.7×	0.004	SH2B3
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	2808.7×	0.004	JAK2
regulation of postsynapse to nucleus signaling pathway	1	2808.7×	0.004	JAK2
monocyte homeostasis	1	1872.4×	0.005	SH2B3
positive regulation of growth hormone receptor signaling pathway	1	1872.4×	0.005	JAK2
collagen-activated signaling pathway	1	1404.3×	0.005	JAK2
granulocyte-macrophage colony-stimulating factor signaling pathway	1	1404.3×	0.005	JAK2
activation of Janus kinase activity	1	1404.3×	0.005	JAK2
negative regulation of receptor signaling pathway via STAT	1	1123.5×	0.005	SH2B3
post-embryonic hemopoiesis	1	936.2×	0.005	JAK2
interleukin-5-mediated signaling pathway	1	936.2×	0.005	JAK2
interleukin-23-mediated signaling pathway	1	936.2×	0.005	JAK2
positive regulation of NK T cell proliferation	1	936.2×	0.005	JAK2
negative regulation of response to cytokine stimulus	1	936.2×	0.005	SH2B3
positive regulation of leukocyte proliferation	1	936.2×	0.005	JAK2
interleukin-3-mediated signaling pathway	1	802.5×	0.006	JAK2
negative regulation of chemokine-mediated signaling pathway	1	802.5×	0.006	SH2B3
interleukin-12-mediated signaling pathway	1	624.1×	0.006	JAK2
mammary gland epithelium development	1	624.1×	0.006	JAK2
response to hydroperoxide	1	561.7×	0.006	JAK2
regulation of nitric oxide biosynthetic process	1	561.7×	0.006	JAK2
neutrophil homeostasis	1	510.7×	0.006	SH2B3
growth hormone receptor signaling pathway via JAK-STAT	1	510.7×	0.006	JAK2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
JAK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK2	100	4
SH2B3	0	0
EPOR	0	0
INSL6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	JAK2
RUXOLITINIB	4	JAK2
TOFACITINIB	4	JAK2
UPADACITINIB	4	JAK2
MOMELOTINIB	4	JAK2
PONATINIB	4	JAK2
AXITINIB	4	JAK2
NICLOSAMIDE	4	JAK2
RUXOLITINIB PHOSPHATE	4	JAK2
INFIGRATINIB PHOSPHATE	4	JAK2
INFIGRATINIB	4	JAK2
ENTRECTINIB	4	JAK2
DABRAFENIB	4	JAK2
PACRITINIB	4	JAK2
TOFACITINIB CITRATE	4	JAK2
BARICITINIB	4	JAK2
CERITINIB	4	JAK2
BOSUTINIB	4	JAK2
PEFICITINIB	4	JAK2
LORLATINIB	4	JAK2
FILGOTINIB	4	JAK2
BRIGATINIB	4	JAK2
ABROCITINIB	4	JAK2
REPOTRECTINIB	4	JAK2
DEUCRAVACITINIB	4	JAK2
PRALSETINIB	4	JAK2
CRAVACITINIB	4	JAK2
PAZOPANIB	4	JAK2
NINTEDANIB	4	JAK2
SUNITINIB	4	JAK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
JAK2	2,018	Binding:1911, Functional:51, ADMET:48, Unclassified:4, Toxicity:4
EPOR	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
JAK2	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
JAK2	2,018

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
FEDRATINIB	4	JAK2
RUXOLITINIB	4	JAK2
TOFACITINIB	4	JAK2
UPADACITINIB	4	JAK2
MOMELOTINIB	4	JAK2
PONATINIB	4	JAK2
AXITINIB	4	JAK2
NICLOSAMIDE	4	JAK2
RUXOLITINIB PHOSPHATE	4	JAK2
INFIGRATINIB PHOSPHATE	4	JAK2
INFIGRATINIB	4	JAK2
ENTRECTINIB	4	JAK2
DABRAFENIB	4	JAK2
PACRITINIB	4	JAK2
TOFACITINIB CITRATE	4	JAK2
BARICITINIB	4	JAK2
CERITINIB	4	JAK2
BOSUTINIB	4	JAK2
PEFICITINIB	4	JAK2
LORLATINIB	4	JAK2
FILGOTINIB	4	JAK2
BRIGATINIB	4	JAK2
ABROCITINIB	4	JAK2
REPOTRECTINIB	4	JAK2
DEUCRAVACITINIB	4	JAK2
PRALSETINIB	4	JAK2
CRAVACITINIB	4	JAK2
PAZOPANIB	4	JAK2
NINTEDANIB	4	JAK2
SUNITINIB	4	JAK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	JAK2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	EPOR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SH2B3, INSL6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SH2B3	0	JAK2
EPOR	9	JAK2
INSL6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.