TTR

Chr 18

transthyretin

Also known as: AMYLD1, ATTR, CTS, CTS1, HEL111, HsT2651, PALB, TBPA

NCBI Gene: 7276 ENSG00000118271 UniProt: P02766

Transthyretin is a tetrameric carrier protein that transports thyroid hormones in plasma and cerebrospinal fluid and also transports retinol (vitamin A) by associating with retinol-binding protein. Mutations cause autosomal dominant hereditary transthyretin amyloidosis, which predominantly affects peripheral nerves and heart, as well as dystransthyretinemic hyperthyroxinemia and familial carpal tunnel syndrome. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.763), and amyloidosis typically presents in adulthood with progressive polyneuropathy or cardiomyopathy.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

GeneReviews ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.76

Clinical Summary— TTR

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Gene-Disease Validity (ClinGen)

obsolete hereditary ATTR amyloidosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.52) — some intolerance to loss-of-function variants.

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ClinVar Variants

133 unique Pathogenic / Likely Pathogenic· 141 VUS of 444 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TTR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.76LOEUF

pLI 0.516

Z-score 1.94

OE 0.16 (0.06–0.76)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.01Z-score

OE missense 0.69 (0.55–0.86)

57 obs / 83.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.06–0.76)

0≤0.351.4

Missense OE?0.69 (0.55–0.86)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 1 / 6.2Missense obs/exp: 57 / 83.0Syn Z: 0.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTTR-related hereditary transthyretin (ATTR) amyloidosisGOFAD

This gene — mechanism propensity

0.2598th %ile

GOF

0.4085th %ile

LOF

0.3163th %ile

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFResults showed that TTR haploinsufficiency (TTR+/-) leads to higher glucose in both plasma and in primary hepatocyte culture media and lower expression of the influx glucose transporters, GLUT1, GLUT3, and GLUT4.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 34199897 ↗

ClinVar Variant Classifications

444 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55

Likely Pathogenic78

VUS141

Likely Benign114

Benign12

Conflicting43

Pathogenic

Likely Pathogenic

141

VUS

114

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	55	0	0	55
Likely Pathogenic	0	78	0	0	78
VUS	20	93	26	2	141
Likely Benign	0	3	47	64	114
Benign	0	0	11	1	12
Conflicting	—				43
Total	20	229	84	67	443

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

40 pathogenic / likely-pathogenic (of 52) ClinVar copy-number / structural variants overlap TTR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TTR · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — TTR

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

B-cell Non Hodgkin Lymphoma (NHL)DLBCL - Diffuse Large B Cell LymphomaFollicular Lymphoma (FL)

A Clinical Study Exploring the Safety, Efficacy and Metabolic Kinetics of CT1182 Injection in Patients With Relapsed / Refractory Non Hodgkin Lymphoma

RECRUITING

NCT07548697Phase EARLY_PHASE1Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyStarted 2026-04-30

CT1182 injection

Transthyretin AmyloidosisATTR-CMATTRv-PN

Non-interventional Study of Patients With Transthyretin (ATTR) Amyloidosis

RECRUITING

NCT06465810AstraZenecaStarted 2024-06-25

Treatment of transthyretin (ATTR) amyloidosis in observational study setting

Breast Cancer Early Stage Breast Cancer (Stage 1-3)Prehabilitation

Multimodal Prehabilitation Program That Combines Physical Exercise, Psychological Intervention and Nutritional Support to Improve the Response to Neoadjuvant Chemoterhapy in Early Breast Cancer Patients

RECRUITING

NCT07107594Phase NAHospital Clinic of BarcelonaStarted 2025-01-14

Multimodal prehabilitation

Diffuse Large B Cell Lymphoma

Selinexor in Combination With R-CHOP as the First-line Therapy for TP53-mutated DLBCL Patients (Smart Trial)

RECRUITING

NCT06517511Phase PHASE2Sun Yat-sen UniversityStarted 2024-08-01

Selinexor Oral Tablet [Xpovio]R-CHOP Protocol

HER2-positive Breast Cancer

PHESGO Maintenance After T-DXd Short Induction for HER2+ Unresectable Locally Recurrent or Metastatic Breast Cancer

ACTIVE NOT RECRUITING

NCT06172127Phase PHASE2MedSIRStarted 2024-07-22

Trastuzumab deruxtecanPhesgo 1,200 MG / 600 MG / 30,000 UNT Per 15 ML InjectionPhesgo 600 MG / 600 MG / 20,000 UNT in 10 mL Injection

CardiomyopathiesAmyloidosis CardiacFabry Disease

Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation

RECRUITING

NCT06813443IRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2023-02-13

Non-small Cell Lung Cancer

A Trial to Learn How the Combination of Fianlimab With Cemiplimab and Chemotherapy Works Compared With Cemiplimab and Chemotherapy for Treating Adult Patients With Advanced Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING

NCT05800015Phase PHASE2, PHASE3Regeneron PharmaceuticalsStarted 2023-08-08

fianlimabcemiplimabPemetrexed

Breast Cancer

Trial of Perioperative Endocrine Therapy - Individualising Care

ACTIVE NOT RECRUITING

NCT02338310Phase PHASE3Institute of Cancer Research, United KingdomStarted 2008-09

Aromatase Inhibitors

Advanced Thyroid Cancer Patients Who Received Target Therapy

A Retrospective and Prospective Real-world Study of Molecular Typing in the Treatment of Advanced Thyroid Cancer

RECRUITING

NCT06195228Phase PHASE4Fudan UniversityStarted 2020-01-01