GeneBe

HJV

protein-coding

hemojuvelin BMP co-receptor, the group of Repulsive guidance molecule family

Gene summary

The product of this gene is involved in iron metabolism. It may be a component of the signaling pathway which activates hepcidin or it may act as a modulator of hepcidin expression. It could also represent the cellular receptor for hepcidin. Two uORFs in the 5' UTR negatively regulate the expression and activity of the encoded protein. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Defects in this gene are the cause of hemochromatosis type 2A, also called juvenile hemochromatosis (JH). JH is an early-onset autosomal recessive disorder due to severe iron overload resulting in hypogonadotrophic hypogonadism, hepatic fibrosis or cirrhosis and cardiomyopathy, occurring typically before age of 30. [provided by RefSeq, Oct 2015]

Previous symbols:
  • HFE2

MANE transcript

NM_213653.4

Inheritance

AR

ClinVar variants

P:89U:136B:206

Top phenotype

Hemochromatosis, type 2A

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr1:146,017,468-146,036,746

External References & Databases

Ensembl (ENSG00000168509)NCBI Gene (148738)OMIM (608374)HGNC:4887GenCCUniProt (Q6ZVN8)AlphaFoldClinVar (HJV)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~19.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemochromatosis type 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011216

Submitter: ClinGen

*HJV* was first reported in relation to autosomal recessive hemochromatosis type 2A in 2004 (Papanikolaou G et al. PMID:14647275). The disease is characterized by an early onset (usually 20s-30s) of iron overload resulting in cardiomyopathy, diabetes and hypogonadism. Eleven unique variants (6 missense, 4 nonsense and 1 frameshift) that have been reported in 17 probands in 3 publications (PMIDs: 14647275, 14982873, 40587672) are included in this curation. Several more missense and frameshift variants are reported in the literature. Four affected segregations from two families are scored in this curation (PMID:14647275) and more families are reported. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and a protein association assay (PMIDs: 19252486, 16075059, 24309898, 25970244, 14647275). Expression studies demonstrate specific expression of *HJV* in the liver and small intestine (PMIDs:14647275, 24309898, 25970244). An assay demonstrates a direct association of *HJV* with BMP6, which has been previously curated by this GCEP to be implicated in the phenotype (CCID:008849; PMID:19252486). Two different mouse models, one that knocks out *HJV* with a targeted vector and one that administers *HJV.Fc*, have shown that without functional *HJV* mice demonstrate iron accumulation in the liver resulting in a hematological and histopathological phenotype that is similar to that of humans (PMIDs:19252486, 16075059). There may be more experimental evidence available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between *HJV* and autosomal recessive hemochromatosis type 2A. This evidence has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date July 11, 2025 (SOP Version 11).

hemochromatosis type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011216

Submitter: Labcorp Genetics (formerly Invitae)

hemochromatosis type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019257

Submitter: Orphanet

hemochromatosis type 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011216

Submitter: Natera

hemochromatosis type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011216

Submitter: PanelApp Australia

hemochromatosis type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011216

Submitter: Genomics England PanelApp

hemochromatosis type 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011216

Submitter: G2P

Clinical Genomic Database (CGD)

Hemochromatosis, type 2AAR

Manifestation: Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic

Intervention: Biochemical; Gastrointestinal; Hematologic

Rationale: Patients may benefit from surveillance related to iron overload, and from interventions such as venesection; Certain agents should be avoided (eg, alcohol consumption; iron-containing compounds; uncooked seafood); Hormone therapy may be beneficial in order to prevent osteoporosis

Comments: Variants may also modify the severity of HFE-related hemochromatosis

Refs: 10205270; 12891378; 14982873; 15254010; 14982867; 14647275; 15461631; 15811010; 17847004; 18492090; 19796184; 20301349Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HJV variants in ClinVar

9 Conditions Cataloged
not providedTotal: 339
Hemochromatosis type 2ATotal: 130
not specifiedTotal: 70
HJV-related disorderTotal: 16
Juvenile hemochromatosisTotal: 2
Hemochromatosis type 1Total: 2
HFE2 & HJV-related disordersTotal: 1
HFE2-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_213653.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
200
clinvar
2
clinvar
 209
missense
4
clinvar
16
clinvar
126
clinvar
3
clinvar
1
clinvar
 150
nonsense
13
clinvar
8
clinvar
1
clinvar
 22
start loss
5
clinvar
 5
frameshift
20
clinvar
15
clinvar
 35
splice donor/acceptor (+/-2bp)
2
clinvar
6
clinvar
2
clinvar
 10
Total39501362033431

Highest pathogenic variant AF is 0.00042193203

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_213653.4RefSeqNP_998818.13MANE Select
ENST00000336751.11EnsemblENSP00000337014.53MANE Select
NM_001316767.2RefSeqNP_001303696.11Standard
NM_001379352.1RefSeqNP_001366281.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hjvDanio rerio

Structure: whole organism

Quality: undulate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Hfe effect on hepcidin production
  • Developmental Biology
  • BMP receptor signaling
  • Netrin-1 signaling
  • Axon guidance

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • cellular iron ion homeostasis
  • protein autoprocessing
  • BMP signaling pathway
  • negative regulation of BMP signaling pathway

Molecular Function

  • signaling receptor binding
  • protein binding
  • coreceptor activity
  • BMP binding
  • BMP receptor activity

Cellular Component

  • extracellular space
  • plasma membrane
  • cell surface
  • anchored component of membrane
  • BMP receptor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000336751
Coding exons
3
Length
4451
Individuals with no LoFs
125723
Homozygous LoFs
0
Heterozygous LoFs
25
Defined
125748
p
0.0000994
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1522472401.030.00001312710
Missense (PolyPhen)9894.6731.03511158
Synonymous0.4309297.40.9450.00000497973
Loss of Function1.89613.50.4459.27e-7129

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish00.0absent
European (Non-Finnish)0.000120.00012rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as a bone morphogenetic protein (BMP) coreceptor. Through enhancement of BMP signaling regulates hepcidin (HAMP) expression and regulates iron homeostasis. {ECO:0000250|UniProtKB:Q7TQ32}.;
Disease
DISEASE: Hemochromatosis 2A (HFE2A) [MIM:602390]: A juvenile form of hemochromatosis, a disorder of iron metabolism with excess deposition of iron in a variety of organs leading to their failure, bronze skin pigmentation, hepatic cirrhosis, arthropathy and diabetes. The most common symptoms of juvenile hemochromatosis at presentation are hypogonadism and cardiomyopathy. {ECO:0000269|PubMed:14647275, ECO:0000269|PubMed:14982867, ECO:0000269|PubMed:14982873, ECO:0000269|PubMed:15461631}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.239

Intolerance Scores

RVIS EVS
-0.34
RVIS percentile EVS
30.56

Essentials

Essential (gene trap)
N
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