EGLN1

egl-9 family hypoxia inducible factor 1, the group of Zinc fingers MYND-type

Basic information

Region (hg38): 1:231363750-231422287

Previous symbols: [ "C1orf12" ]

Links

ENSG00000135766 ∙ NCBI:54583 ∙ OMIM:606425 ∙ HGNC:1232 ∙ Uniprot:Q9GZT9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• erythrocytosis, familial, 3 (Strong), mode of inheritance: AD
• autosomal dominant secondary polycythemia (Supportive), mode of inheritance: AD
• erythrocytosis, familial, 3 (Limited), mode of inheritance: AD
• hemoglobin, high altitude adaptation (Limited), mode of inheritance: AD
• erythrocytosis, familial, 3 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Erythrocytosis, familial, 3	AD	Hematologic; Oncologic	Phlebotomy can be used to maintain the hematocrit value in the desired range; Due to a reported increased risk of neoplasms, awareness may allow early detection and management, which may decrease associated morbidity and mortality	Hematologic; Oncologic	16407130; 17579185; 19092153; 20301715; 20466884; 20595611; 21275967; 21828119; 21904933; 25129147
In some described individuals, it has been suggested that manifestations involved increased risk of neoplasms as well as hematologic manifestations

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EGLN1 gene.

• Hereditary cancer-predisposing syndrome (623 variants)
• Erythrocytosis, familial, 3 (324 variants)
• not provided (29 variants)
• Inborn genetic diseases (16 variants)
• Familial erythrocytosis (13 variants)
• not specified (4 variants)
• Erythrocytosis, familial, 3;Hemoglobin, high altitude adaptation (2 variants)
• Hemoglobin, high altitude adaptation;Erythrocytosis, familial, 3 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EGLN1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	292	1	294
missense			382	7	3	392
nonsense	1					1
start loss			2			2
frameshift	1		1			2
inframe indel			7	1		8
splice donor/acceptor (+/-2bp)						0
splice region			1	3	2	6
non coding			44	26	28	98
Total	2	0	437	326	32

Highest pathogenic variant AF is 0.00000658

Variants in EGLN1

This is a list of pathogenic ClinVar variants found in the EGLN1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-231363813-C-T		Erythrocytosis, familial, 3	Benign (Jan 12, 2018)
1-231363834-C-G		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231363920-G-A		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231363991-CACAA-C		Familial erythrocytosis	Likely benign (Jun 14, 2016)
1-231364176-G-C		Erythrocytosis, familial, 3	Benign (Jan 13, 2018)
1-231364315-A-G		Erythrocytosis, familial, 3	Benign (Jan 12, 2018)
1-231364350-G-C		Erythrocytosis, familial, 3	Benign (Apr 27, 2017)
1-231364367-C-T		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231364368-G-A		Erythrocytosis, familial, 3	Likely benign (Apr 27, 2017)
1-231364388-T-C		Erythrocytosis, familial, 3	Uncertain significance (Jan 12, 2018)
1-231364446-T-C		Familial erythrocytosis	Uncertain significance (Jun 14, 2016)
1-231364492-A-G		Erythrocytosis, familial, 3	Benign (Jan 13, 2018)
1-231364500-G-A		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231364531-T-A		Erythrocytosis, familial, 3	Benign (Jan 13, 2018)
1-231364557-A-C		Erythrocytosis, familial, 3	Uncertain significance (Jan 12, 2018)
1-231364586-C-T		Erythrocytosis, familial, 3	Uncertain significance (Jan 15, 2018)
1-231364607-A-ATT		Familial erythrocytosis	Uncertain significance (Jun 14, 2016)
1-231364624-A-C		Erythrocytosis, familial, 3	Likely benign (Apr 27, 2017)
1-231364680-G-A		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231364924-G-A		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231364974-TAAG-T		Familial erythrocytosis	Likely benign (Jun 14, 2016)
1-231364981-ACC-A		Familial erythrocytosis	Uncertain significance (Jun 14, 2016)
1-231364991-CAAAAT-C		Familial erythrocytosis	Uncertain significance (Jun 14, 2016)
1-231365085-A-G		Erythrocytosis, familial, 3	Uncertain significance (Jan 13, 2018)
1-231365123-G-A		Erythrocytosis, familial, 3	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EGLN1	protein_coding	protein_coding	ENST00000366641	5	61294

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.974	0.0260	125716	0	3	125719	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.15	119	206	0.578	0.0000107	2728
Missense in Polyphen		15	72.209	0.20773		844
Synonymous	-2.09	109	84.6	1.29	0.00000463	850
Loss of Function	3.43	1	15.7	0.0639	8.39e-7	184

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.00000880	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15897452, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:21792862, ECO:0000269|PubMed:25129147}.
• Disease: DISEASE: Erythrocytosis, familial, 3 (ECYT3) [MIM:609820]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. {ECO:0000269|PubMed:16407130, ECO:0000269|PubMed:17579185}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Renal cell carcinoma - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);The oncogenic action of Succinate;The oncogenic action of Fumarate;Photodynamic therapy-induced HIF-1 survival signaling;Hereditary Leiomyomatosis and Renal Cell Carcinoma Pathway;Type 2 papillary renal cell carcinoma;Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha;Regulation of Hypoxia-inducible Factor (HIF) by oxygen;Cellular response to hypoxia;Cellular responses to stress;HIF-2-alpha transcription factor network;Hypoxic and oxygen homeostasis regulation of HIF-1-alpha;Cellular responses to external stimuli;HIF-1-alpha transcription factor network (Consensus)

Recessive Scores

• pRec: 0.0955

Haploinsufficiency Scores

• pHI: 0.772
• hipred: Y
• hipred_score: 0.751
• ghis: 0.602

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.343

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Egln1
• Phenotype: growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype; muscle phenotype; homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; renal/urinary system phenotype

Gene ontology

• Biological process: response to hypoxia;cellular iron ion homeostasis;peptidyl-proline hydroxylation to 4-hydroxy-L-proline;oxygen homeostasis;negative regulation of DNA-binding transcription factor activity;regulation of angiogenesis;positive regulation of transcription by RNA polymerase II;negative regulation of cyclic-nucleotide phosphodiesterase activity;cardiac muscle tissue morphogenesis;oxidation-reduction process;heart trabecula formation;ventricular septum morphogenesis;labyrinthine layer development;regulation of transcription from RNA polymerase II promoter in response to hypoxia;response to nitric oxide;regulation of postsynapse organization;regulation of protein catabolic process at postsynapse, modulating synaptic transmission;regulation of neuron death
• Cellular component: nucleus;cytoplasm;cytosol;postsynaptic density;glutamatergic synapse
• Molecular function: protein binding;ferrous iron binding;2-oxoglutarate-dependent dioxygenase activity;enzyme binding;L-ascorbic acid binding;peptidyl-proline dioxygenase activity;peptidyl-proline 4-dioxygenase activity