AVPR2
protein-codingarginine vasopressin receptor 2, the group of Arginine vasopressin and oxytocin receptors
Gene summary
This gene encodes the vasopressin receptor, type 2, also known as the V2 receptor, which belongs to the seven-transmembrane-domain G protein-coupled receptor (GPCR) superfamily, and couples to Gs thus stimulating adenylate cyclase. The subfamily that includes the V2 receptor, the V1a and V1b vasopressin receptors, the oxytocin receptor, and isotocin and mesotocin receptors in non-mammals, is well conserved, though several members signal via other G proteins. All bind similar cyclic nonapeptide hormones. The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these 'extrarenal receptors' are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known - its absence does not appear to be detrimental in NDI patients. The gene expression has also been described in fetal lung tissue and lung cancer associated with alternative splicing. [provided by RefSeq, Jul 2008]
- DIR3
- DIR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010356
Submitter: ClinGen
*AVPR2* was first reported in relation to Nephrogenic syndrome of inappropriate antidiuresis in 2005 (Feldman et al; PMID: 15872203). NSIAD is characterized by an inability to excrete a free water load with undetectable levels of AVP (PMID: 15872203), resulting in inappropriately concentrated urine, hyponatremia, hypo-osmolality, and natriuresis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, nephrogenic diabetes insipidus (OMIM: 304800), nephrogenic syndrome of inappropriate antidiuresis (OMIM: 300539) accounting for the loss of function variants observed in NDI and the gain-of-function variants observed in NSIAD which results in hypernatremic and hyponatremic dehydration respectively. The split curation for Nephrogenic syndrome of inappropriate antidiuresis has been curated separately. Five missense variants that have been reported in five probands in four publications (PMIDs: 26131744, 22956819, 27355191, 15872203) are included in this curation and a genetic evidence score of 7 pts was reached. The mechanism of pathogenicity is known to be gain-of-function of the V2 receptor by increasing AQP2 membrane localization. This gene-disease association is also supported expression studies in humans, in vitro functional assays of AQP2 localization, and cryo-electron functional studies (PMIDs: 17626156, 31486901, 34020960, 26077742). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 8/19/2021 (SOP Version 8).
Inheritance Pattern: XL
Disease ID:MONDO:0010581
Submitter: ClinGen
*AVPR2* was first reported in relation to X-linked nephrogenic diabetes insipidus (NDI) in 1992 (Rosenthal, et al 1992, PMID: 1356229). NDI is characterized by the inability to concentrate urine despite normal or elevated antidiuretic hormone, arginine vasopressin, and results in polyuria, and polydipsia. When untreated, this condition results in severe bouts of dehydration. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, nephrogenic diabetes insipidus (OMIM: 304800), and nephrogenic syndrome of inappropriate antidiuresis (OMIM: 300539). This accounts for the loss-of-function variants observed in NDI and the gain-of-function variants observed in NSIAD, which result in hypernatremic and hyponatremic dehydration, respectively. The split curation for X-linked nephrogenic syndrome of inappropriate antidiuresis has been curated separately. Over 100 variants have been reported in patients with NDI. 13 variants (missense, nonsense, frameshift, indel) that have been reported in 13 probands in 5 publications (PMIDs: 1356229, 7913579, 7933835, 24026507, 33009446) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is known to be loss-of-function of the V2 receptor by protein misfolding and endoplasmic reticulum retention, unstable mRNA, or decreased affinity for AVP binding. This gene-disease association is also supported by animal loss-of-function models, expression studies in humans and mice model, as well as in vitro functional assays of cAMP generation and protein mis-localization (PMIDs: 17626156, 11104789, 16006591). In summary, *AVPR2* is definitively associated with X-linked nephrogenic diabetes insipidus. This 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 Tubulopathy GCEP on the meeting date 8/19/2021 (SOP Version 8).
Inheritance Pattern: XL
Disease ID:MONDO:0010581
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010356
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010356
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010356
Submitter: Orphanet
Inheritance Pattern: XLR
Disease ID:MONDO:0010356
Submitter: Natera
Inheritance Pattern: XLR
Disease ID:MONDO:0016383
Submitter: Natera
Inheritance Pattern: AD
Disease ID:MONDO:0016383
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010581
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010581
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010356
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Renal
Intervention: Endocrine; Renal
Rationale: In Diabetes insipidus, nephrogenic, X-linked, sequelae may be prevented with early genetic knowledge to allow management of electrolyte and fluid balances (eg, with specific diuretics) has been reported as potentially beneficial); In Nephrogenic syndrome of inappropriate antidiuresis, patients can have electrolyte and fluid imbalances, and management of these issues through initial fluid restriction and osmotic agents) have been reported to be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AVPR2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000054.7. 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 | 7 | 103 | 5 | 115 | ||
| missense | 19 | 44 | 106 | 36 | 8 | 213 |
| nonsense | 15 | 2 | 1 | 18 | ||
| start loss | 0 | |||||
| frameshift | 26 | 20 | 46 | |||
| splice donor/acceptor (+/-2bp) | 4 | 4 | 8 | |||
| Total | 64 | 66 | 118 | 139 | 13 | 400 |
Highest pathogenic variant AF is 0.0000027537892
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000045.1 | 3 | MANE Select | |
| Ensembl | ENSP00000496396.1 | 3 | MANE Select | |
| RefSeq | NP_001139623.1 | 2 | Standard | |
| Ensembl | ENSP00000338072.5 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vasopressin-regulated water reabsorption - Homo sapiens (human)
- Phospholipase D signaling pathway - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- Vasopressin Regulation of Water Homeostasis
- Peptide GPCRs
Biological Process
- regulation of systemic arterial blood pressure by vasopressin
- positive regulation of systemic arterial blood pressure
- renal water homeostasis
- G protein-coupled receptor signaling pathway
- adenylate cyclase-modulating G protein-coupled receptor signaling pathway
Molecular Function
- vasopressin receptor activity
- protein binding
Cellular Component
- endosome
- endoplasmic reticulum
- Golgi apparatus
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000358927
- Coding exons
- 3
- Length
- 4636
- Individuals with no LoFs
- 125386
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125387
- p
- 0.00000399
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.01 | 148 | 187 | 0.792 | 0.0000178 | 2337 |
| Missense (PolyPhen) | 47 | 81.69 | 0.57534 | 1143 | ||
| Synonymous | -1.10 | 91 | 78.6 | 1.16 | 0.00000710 | 851 |
| Loss of Function | 2.03 | 1 | 6.63 | 0.151 | 4.22e-7 | 99 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000072 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption. {ECO:0000269|PubMed:19440390}.;
- Disease
- DISEASE: Diabetes insipidus, nephrogenic, X-linked (XNDI) [MIM:304800]: A disorder caused by the inability of the renal collecting ducts to absorb water in response to arginine vasopressin. Characterized by excessive water drinking (polydipsia), excessive urine excretion (polyuria), persistent hypotonic urine, and hypokalemia. {ECO:0000269|PubMed:10694923, ECO:0000269|PubMed:10770218, ECO:0000269|PubMed:11026555, ECO:0000269|PubMed:11232028, ECO:0000269|PubMed:11916004, ECO:0000269|PubMed:1303257, ECO:0000269|PubMed:1303271, ECO:0000269|PubMed:1356229, ECO:0000269|PubMed:16845277, ECO:0000269|PubMed:7560098, ECO:0000269|PubMed:7833930, ECO:0000269|PubMed:7984150, ECO:0000269|PubMed:7987330, ECO:0000269|PubMed:7999078, ECO:0000269|PubMed:8037205, ECO:0000269|PubMed:8045948, ECO:0000269|PubMed:8078903, ECO:0000269|PubMed:8267567, ECO:0000269|PubMed:8479490, ECO:0000269|PubMed:8514744, ECO:0000269|PubMed:9402087, ECO:0000269|PubMed:9452109, ECO:0000269|PubMed:9711877}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.589
Intolerance Scores
- LoFtool
- 0.104
- RVIS EVS
- 1.09
- RVIS percentile EVS
- 91.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.731
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |