PTH

protein-coding

parathyroid hormone, the group of Receptor ligands

Gene summary

This gene encodes a member of the parathyroid family of proteins. The encoded preproprotein is proteolytically processed to generate a protein that binds to the parathyroid hormone/parathyroid hormone-related peptide receptor and regulates blood calcium and phosphate levels. Excess production of the encoded protein, known as hyperparathyroidism, can result in hypercalcemia and kidney stones. On the other hand, defective processing of the encoded protein may lead to hypoparathyroidism, which can result in hypocalcemia and numbness. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

MANE transcript

NM_000315.4

Inheritance

AD, AR

ClinVar variants

P:10U:26B:7

Top phenotype

Hypoparathyroidism, familial isolated 1

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr11:13,492,054-13,496,181

External References & Databases

Ensembl (ENSG00000152266)

Transcript & Mutation Effects

hg38 • Region Span ~4.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypoparathyroidism, familial isolated 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007796

Submitter: PanelApp Australia

familial isolated hypoparathyroidism due to impaired PTH secretionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016000

Submitter: Orphanet

hypoparathyroidism, familial isolated 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007796

Submitter: G2P

hypoparathyroidism, familial isolated 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007796

Submitter: Labcorp Genetics (formerly Invitae)

hypoparathyroidism, familial isolated 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007796

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypoparathyroidism, familial isolated 1AD/AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Early recognition of electrolyte abnormalitities (eg, hypocalcemia) can allow prompt treatment in order to avoid severe sequelae

Refs: 3005800; 2212001; 1302009; 10523031

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTH variants in ClinVar

6 Conditions Cataloged

not providedTotal: 20

not specifiedTotal: 13

Hypoparathyroidism, familial isolated 1Total: 10

Familial hypoparathyroidismTotal: 6

PTH-related disorderTotal: 4

Primary hyperparathyroidismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000315.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				3 clinvar	2 clinvar	5
missense	1 clinvar	4 clinvar	26 clinvar	2 clinvar		33
nonsense		1 clinvar				1
start loss		1 clinvar				1
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	2	8	26	5	2	43

Highest pathogenic variant AF is 0.000008058358

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000315.4	RefSeq	NP_000306.1	2	MANE Select
ENST00000282091.6	Ensembl	ENSP00000282091.1	2	MANE Select
NM_001316352.2	RefSeq	NP_001303281.1	3	Standard
ENST00000529816.1	Ensembl	ENSP00000433208.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pth1a	Danio rerio	Structure: ceratohyal cartilage Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

pth1a

Danio rerio

Structure: ceratohyal cartilage

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vitamin D Metabolism
Vitamin D Receptor Pathway
Osteoblast Signaling
Endochondral Ossification
Signaling by GPCR

Biological Process

negative regulation of transcription by RNA polymerase II
skeletal system development
calcium ion transport
cellular calcium ion homeostasis
G protein-coupled receptor signaling pathway

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
hormone activity
parathyroid hormone receptor binding
type 1 parathyroid hormone receptor binding
protein N-terminus binding

Cellular Component

extracellular region
extracellular space
cell

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282091
Coding exons: 2
Length: 4127
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125743
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.549	50	62.2	0.804	0.00000302	761
Missense (PolyPhen)		20	18.608	1.0748		255
Synonymous	-0.0435	22	21.7	1.01	0.00000108	217
Loss of Function	0.496	3	4.08	0.735	2.57e-7	46

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: PTH elevates calcium level by dissolving the salts in bone and preventing their renal excretion. Stimulates [1-14C]-2- deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblastic cells. {ECO:0000269|PubMed:21076856}.;
Disease: DISEASE: Hypoparathyroidism, familial isolated (FIH) [MIM:146200]: A disorder characterized by hypocalcemia and hyperphosphatemia due to inadequate secretion of parathyroid hormone. Clinical features include seizures, tetany and cramps. {ECO:0000269|PubMed:10523031, ECO:0000269|PubMed:18056632, ECO:0000269|PubMed:2212001}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.954

Intolerance Scores

LoFtool: 0.475
RVIS EVS: -0.08
RVIS percentile EVS: 47.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.534

Gene Damage Prediction

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