Paraganglioma_phaeochromocytoma
Gene: EPAS1EnsemblGeneIds (GRCh38): ENSG00000116016
EnsemblGeneIds (GRCh37): ENSG00000116016
OMIM: 603349, Gene2Phenotype
EPAS1 is in 3 panels
1 review
Chirag Patel (Genetic Health Queensland)
PMID: 22931260
2 somatic gain-of-function variants in EPAS1 gene encoding hypoxia-inducible factor 2α (HIF2A) in two patients (1 x paraganglioma, 1 x paraganglioma + somatostatinoma). Both patients had polycythemia (congenital erythrocytosis). The two variants were associated with increased HIF-2α activity and increased protein half-life.
PMID: 23418310
7 patients with somatic variants in EPAS1 gene (4 x multiple PGLs, 3 x single sporadic PCC/PGL). Gene expression analysis of EPAS1-mutated tumours revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumour and in 3 non-EPAS1-mutated cases.
PMID: 33300499
6 germline missense variants in EPAS1 gene in patients with PPGL (Arg247Ser, Phe374Tyr, His194Arg, Pro785Thr, Ile789Val, Thr766Pro). In transient transfection studies, EPAS1/HIF-2α Arg247Ser, Phe374Tyr and Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the Arg247Ser variant showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α Phe374Tyr and Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Their findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.
Sources: Expert list, Expert Review, LiteratureCreated: 18 Sep 2024, 10:06 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Pheochromocytoma/paraganglioma, susceptibility to, no MIM#; Erythrocytosis, familial, 4, MIM#611783
Publications
Details
- Mode of Inheritance
- MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
- Sources
-
- Expert Review Red
- Literature
- Expert Review
- Expert list
- Phenotypes
-
- Paraganglioma, MONDO:0000448
- Pheochromocytoma, MONDO:0008233
- Pheochromocytoma/paraganglioma, susceptibility to, no MIM#
- Erythrocytosis, familial, 4, MIM#611783
- OMIM
- 603349
- Clinvar variants
- Variants in EPAS1
- Penetrance
- None
- Publications
- Panels with this gene
History Filter Activity
Entity classified by Genomics England curator
Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)Gene: epas1 has been classified as Red List (Low Evidence).
Set publications
Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)Publications for gene: EPAS1 were set to PMID: 22931260, 23418310, 33300499
Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes
Chirag Patel (Genetic Health Queensland)gene: EPAS1 was added gene: EPAS1 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature Mode of inheritance for gene: EPAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EPAS1 were set to PMID: 22931260, 23418310, 33300499 Phenotypes for gene: EPAS1 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Pheochromocytoma/paraganglioma, susceptibility to, no MIM#; Erythrocytosis, familial, 4, MIM#611783 Review for gene: EPAS1 was set to RED