TG

protein-coding

thyroglobulin

Gene summary

Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]

MANE transcript

NM_003235.5

Inheritance

AR, AD

ClinVar variants

P:254U:583B:874

Top phenotype

Thyroid dyshormonogenesis 3

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr8:132,866,958-133,134,903

External References & Databases

Ensembl (ENSG00000042832)

Transcript & Mutation Effects

hg38 • Region Span ~267.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thyroid dyshormonogenesis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010135

Submitter: PanelApp Australia

thyroid dyshormonogenesis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010135

Submitter: Labcorp Genetics (formerly Invitae)

familial thyroid dyshormonogenesisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010132

Submitter: Orphanet

thyroid cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0002108

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Thyroid dyshormonogenesis 3AR

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: Medical treatment of hypothyroidism (eg, with T4) can be effective ; Thyroid neoplasms have also been reported, and surveillance may be beneficial to allow early treatment

Refs: 2584351; 1752952; 14657345; 14557492; 14764776; 16187918; 16403815; 16720658; 16477365; 17244789

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TG variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1554

Inborn genetic diseasesTotal: 435

Iodotyrosyl coupling defectTotal: 357

not specifiedTotal: 168

Autoimmune thyroid disease, susceptibility to, 3Total: 79

TG-related disorderTotal: 69

Congenital hypothyroidismTotal: 26

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003235.5. 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		1 clinvar	3 clinvar	760 clinvar	10 clinvar	774
missense	5 clinvar	12 clinvar	567 clinvar	99 clinvar	5 clinvar	688
nonsense	84 clinvar	20 clinvar	2 clinvar			106
start loss			1 clinvar			1
frameshift	51 clinvar	25 clinvar	3 clinvar			79
splice donor/acceptor (+/-2bp)	9 clinvar	47 clinvar	7 clinvar			63
Total	149	105	583	859	15	1711

Highest pathogenic variant AF is 0.0011795785

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003235.5	RefSeq	NP_003226.4	48	MANE Select
ENST00000220616.9	Ensembl	ENSP00000220616.4	48	MANE Select
ENST00000518058.1	Ensembl	ENSP00000429164.1	2	Standard
ENST00000518108.1	Ensembl	ENSP00000429761.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone synthesis - Homo sapiens (human)
Autoimmune thyroid disease - Homo sapiens (human)
Thyroid hormone synthesis
Thyroxine (Thyroid Hormone) Production

Biological Process

signal transduction
regulation of signaling receptor activity
iodide transport
thyroid gland development
regulation of myelination

Molecular Function

hormone activity

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000220616
Coding exons: 48
Length: 267945
Individuals with no LoFs: 125260
Homozygous LoFs: 1
Heterozygous LoFs: 487
Defined: 125748
p: 0.00194

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.41	1660	1.51e+3	1.10	0.0000914	17985
Missense (PolyPhen)		421	437.6	0.96207		5199
Synonymous	-1.04	633	601	1.05	0.0000380	5512
Loss of Function	2.62	110	144	0.765	0.00000817	1574

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0026	0.0026	notable
Latino/Admixed American	0.0020	0.0020	notable
Ashkenazi Jewish	0.0033	0.0033	notable
East Asian	0.0024	0.0024	notable
Finnish	0.0018	0.0018	notable
European (Non-Finnish)	0.0017	0.0017	notable
South Asian	0.0017	0.0017	notable
Other	0.0024	0.0024	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Precursor of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).;
Disease: DISEASE: Thyroid dyshormonogenesis 3 (TDH3) [MIM:274700]: A disorder due to thyroid dyshormonogenesis, causing large goiters of elastic and soft consistency in the majority of patients. Although the degree of thyroid dysfunction varies considerably among patients with defective thyroglobulin synthesis, patients usually have a relatively high serum free triiodothyronine (T3) concentration with disproportionately low free tetraiodothyronine (T4) level. The maintenance of relatively high free T3 levels prevents profound tissue hypothyroidism except in brain and pituitary, which are dependent on T4 supply, resulting in neurologic and intellectual defects in some cases. {ECO:0000269|PubMed:10199792, ECO:0000269|PubMed:16477365, ECO:0000269|PubMed:17244789, ECO:0000269|PubMed:17532758, ECO:0000269|PubMed:19509106, ECO:0000269|PubMed:27305979}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoimmune thyroid disease 3 (AITD3) [MIM:608175]: A complex autoimmune disorder comprising two related diseases affecting the thyroid: Graves disease and Hashimoto thyroiditis. In both disorders, thyroid-reactive T-cells are formed and infiltrate the thyroid gland. In Graves disease, the majority of the T-cells undergo a Th2 differentiation and activate B-cells to produce antibodies against the TSH receptor, which stimulate the thyroid and cause clinical hyperthyroidism. In contrast, Hashimoto thyroiditis is characterized by Th1 switching of the thyroid- infiltrating T-cells, which induces apoptosis of thyroid follicular cells and clinical hypothyroidism. {ECO:0000269|PubMed:14657345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.858
RVIS EVS: 1.57
RVIS percentile EVS: 95.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.402

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High