GeneBe

VDR

protein-coding

vitamin D receptor, the group of Nuclear receptor subfamily 1 group I|Protein phosphatase 1 regulatory subunits

Gene summary

This gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. This receptor also functions as a receptor for the secondary bile acid, lithocholic acid. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]

MANE transcript

NM_000376.3

Inheritance

AR, AD

ClinVar variants

P:41U:155B:136

Top phenotype

Vitamin D-dependent rickets, type 2A

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr12:47,841,537-47,943,048

External References & Databases

Ensembl (ENSG00000111424)NCBI Gene (7421)OMIM (601769)HGNC:12679GenCCUniProt (P11473)AlphaFoldClinVar (VDR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~101.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vitamin D-dependent rickets, type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010186

Submitter: Labcorp Genetics (formerly Invitae)

vitamin D-dependent rickets, type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010186

Submitter: PanelApp Australia

vitamin D-dependent rickets, type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019642

Submitter: Orphanet

vitamin D-dependent rickets, type 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010186

Submitter: G2P

Clinical Genomic Database (CGD)

Vitamin D-dependent rickets, type 2AAD/AR

Manifestation: Dermatologic; Endocrine; Musculoskeletal

Intervention: Endocrine

Rationale: Treatment of manifestations such as rickets (eg, with vitamin D3, calcium, phosphate) can be beneficial in some individuals, though not all individuals have been reported as demonstrating clinical or laboratory-based response to treatments

Refs: 205789; 233695; 221630; 6102232; 7318845; 3009551; 3024987; 3040300; 2849209; 2551693; 9005998; 17970811; 19815438; 19921089; 21073129; 21424181; 21590741; 21812032; 21860566; 22145479; 22145480; 23026218Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VDR variants in ClinVar

8 Conditions Cataloged
not providedTotal: 350
Vitamin D-dependent rickets type II with alopeciaTotal: 144
Inborn genetic diseasesTotal: 39
not specifiedTotal: 21
VDR-related disorderTotal: 10
RicketsTotal: 1
Hypophosphataemia or ricketsTotal: 1
Familial adenomatous polyposis 2Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000376.3. 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
3
clinvar
122
clinvar
3
clinvar
 128
missense
11
clinvar
11
clinvar
148
clinvar
11
clinvar
 181
nonsense
8
clinvar
2
clinvar
 10
start loss
2
clinvar
 2
frameshift
3
clinvar
1
clinvar
1
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
1
clinvar
 6
Total23181551333332

Highest pathogenic variant AF is 0.000018589502

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000376.3RefSeqNP_000367.18MANE Select
ENST00000549336.6EnsemblENSP00000449573.28MANE Select
NM_001017535.2RefSeqNP_001017535.18Standard
NM_001017536.2RefSeqNP_001017536.110Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
vdrbDanio rerio

Structure: macula saccule

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human)
  • Tuberculosis - Homo sapiens (human)
  • Mineral absorption - Homo sapiens (human)
  • Etoposide Pathway, Pharmacokinetics/Pharmacodynamics
  • NHR

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • cell morphogenesis
  • skeletal system development
  • transcription initiation from RNA polymerase II promoter
  • calcium ion transport

Molecular Function

  • transcription regulatory region sequence-specific DNA binding
  • RNA polymerase II regulatory region sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA binding
  • DNA-binding transcription factor activity

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • receptor complex
  • RNA polymerase II transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000550325
Coding exons
10
Length
101512
Individuals with no LoFs
125738
Homozygous LoFs
0
Heterozygous LoFs
10
Defined
125748
p
0.0000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.062322820.8230.00001833146
Missense (PolyPhen)67105.670.634071149
Synonymous-0.9951211081.120.00000667925
Loss of Function1.981120.70.5300.00000116245

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000650.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells. Enters the nucleus upon vitamin D3 binding where it forms heterodimers with the retinoid X receptor/RXR. The VDR-RXR heterodimers bind to specific response elements on DNA and activate the transcription of vitamin D3-responsive target genes. Recruited to promoters via its interaction with BAZ1B/WSTF which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis. {ECO:0000269|PubMed:10678179, ECO:0000269|PubMed:15728261, ECO:0000269|PubMed:16252006, ECO:0000269|PubMed:16913708, ECO:0000269|PubMed:28698609}.;
Disease
DISEASE: Rickets vitamin D-dependent 2A (VDDR2A) [MIM:277440]: A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets. {ECO:0000269|PubMed:1652893, ECO:0000269|PubMed:17970811, ECO:0000269|PubMed:2177843, ECO:0000269|PubMed:2849209, ECO:0000269|PubMed:28698609, ECO:0000269|PubMed:7828346, ECO:0000269|PubMed:8106618, ECO:0000269|PubMed:8381803, ECO:0000269|PubMed:8392085, ECO:0000269|PubMed:8675579, ECO:0000269|PubMed:8961271, ECO:0000269|PubMed:9005998}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.772

Intolerance Scores

LoFtool
0.0311
RVIS EVS
-0.62
RVIS percentile EVS
17.31

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.951

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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