EPAS1

protein-coding

endothelial PAS domain protein 1, the group of PAS domain containing|Basic helix-loop-helix proteins

Gene summary

This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]

MANE transcript

NM_001430.5

Inheritance

ClinVar variants

P:8U:961B:672

Top phenotype

Erthyrocytosis, familial 4

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr2:46,293,667-46,386,697

External References & Databases

Ensembl (ENSG00000116016)

Transcript & Mutation Effects

hg38 • Region Span ~93.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

erythrocytosis, familial, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012729

Submitter: Genomics England PanelApp

autosomal dominant secondary polycythemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016599

Submitter: Orphanet

erythrocytosis, familial, 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012729

Submitter: Ambry Genetics

erythrocytosis, familial, 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012729

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

erythrocytosis, familial, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012729

Submitter: Labcorp Genetics (formerly Invitae)

erythrocytosis, familial, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012729

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Erthyrocytosis, familial 4AD

Manifestation: Hematologic; Oncologic

Intervention: Hematologic; Oncologic

Rationale: Individuals can present with manifestations secondary to erythrocytosis (eg, a DVT has been described in one individual), and interventions related to erythrocytosis (eg, venesection) have been described as beneficial; Due to a reported increased risk of neoplasms (eg, pheochromocytoma/paraganglioma), awareness may allow early detection and management, which may decrease associated morbidity and mortality

Comments: While presentation is typically described in adulthood, surveillance and treatment may be indicated in the pediatric time period

Refs: 7747773; 18184961; 18456918; 18378852; 23090011

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPAS1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 1549

not providedTotal: 302

Erythrocytosis, familial, 4Total: 83

not specifiedTotal: 56

EPAS1-related disorderTotal: 13

Erythrocytosis, familial, 3Total: 1

TeratomaTotal: 1

Asphyxiating thoracic dystrophy 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001430.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	602 clinvar	1 clinvar	608
missense	4 clinvar	4 clinvar	948 clinvar	67 clinvar	2 clinvar	1025
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	4	4	961	669	3	1641

Highest pathogenic variant AF is 6.8413306e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001430.5	RefSeq	NP_001421.2	16	MANE Select
ENST00000263734.5	Ensembl	ENSP00000263734.3	16	MANE Select
ENST00000449347.5	Ensembl	ENSP00000406137.1	6	Standard
ENST00000861816.1	Ensembl	ENSP00000531875.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
epas1b	Danio rerio	Structure: primary motor neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

epas1b

Danio rerio

Structure: primary motor neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Renal cell carcinoma - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Adipogenesis
Transcriptional regulation of pluripotent stem cells
Amplification and Expansion of Oncogenic Pathways as Metastatic Traits

Biological Process

angiogenesis
response to hypoxia
embryonic placenta development
blood vessel remodeling
regulation of heart rate

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
protein binding
transcription factor binding

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytosol
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263734
Coding exons: 16
Length: 93031
Individuals with no LoFs: 125733
Homozygous LoFs: 1
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.154	490	481	1.02	0.0000299	5752
Missense (PolyPhen)		110	164.02	0.67067		2024
Synonymous	-3.94	276	204	1.35	0.0000140	1662
Loss of Function	4.50	8	37.9	0.211	0.00000203	452

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000065	0.000033	rare
Other	0.00035	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P97481}.;
Disease: DISEASE: Erythrocytosis, familial, 4 (ECYT4) [MIM:611783]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal platelet and leukocyte counts. {ECO:0000269|PubMed:18184961, ECO:0000269|PubMed:18378852, ECO:0000269|PubMed:19208626, ECO:0000269|PubMed:22367913}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.386

Intolerance Scores

LoFtool: 0.0692
RVIS EVS: -0.88
RVIS percentile EVS: 10.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.920

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium