TTR

transthyretin, the group of Gla domain containing

Basic information

Region (hg38): 18:31557008-31598833

Previous symbols: [ "PALB", "CTS1" ]

Links

ENSG00000118271 ∙ NCBI:7276 ∙ OMIM:176300 ∙ HGNC:12405 ∙ Uniprot:P02766 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• heart conduction disease (Strong), mode of inheritance: AD
• familial amyloid neuropathy (Strong), mode of inheritance: AD
• familial amyloid neuropathy (Supportive), mode of inheritance: AD
• ATTRV122I amyloidosis (Supportive), mode of inheritance: AD
• familial amyloid neuropathy (Definitive), mode of inheritance: AD
• hereditary ATTR amyloidosis (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyloidosis, hereditary, transthyretin-related; Hyperthyroxinemia, dystransthyretinemic	AD	Cardiovascular; Endocrine; Gastrointestinal; Neurologic	In Familial transthyretin amyloidosis, surveillance for cardiovascular sequelae (which can include arrhythmias), and earlier treatment (eg, pacemaker) can be beneficial, and liver transplantation may be beneficial especially early in the disease course; Therapies involving transthyretin stabilization, RNA interference, or inhibtion of the hepatic production of transthyretin protein may be beneficial, especially in early stages of disease; In Dystransthyretinemic hyperthyroxinemia, diagnosis may be important in order to avoid unecessary treatment (eg, thyroid ablation)	Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal	13320157; 7417777; 6801514; 3229002; 1979335; 7839813; 8309582; 8784093; 8579098; 9017939; 10523220; 10869060; 11261421; 11385707; 11940682; 14640030; 14986482; 15249622; 15820680; 16357452; 15725588; 17554795; 19075702; 17200500; 18022643; 20301373; 22094129; 22843282; 23193944; 23483184; 23834402; 23901247; 23931808; 23984729; 23984729; 23993291; 24000164; 24023270; 24053266; 29972757

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TTR gene.

• Amyloidogenic transthyretin amyloidosis (264 variants)
• Cardiovascular phenotype (134 variants)
• not provided (108 variants)
• not specified (54 variants)
• Cardiomyopathy (31 variants)
• Charcot-Marie-Tooth disease (29 variants)
• Amyloidogenic transthyretin amyloidosis;Hyperthyroxinemia, dystransthyretinemic;Carpal tunnel syndrome 1 (12 variants)
• Hyperthyroxinemia, dystransthyretinemic;Carpal tunnel syndrome 1;Amyloidogenic transthyretin amyloidosis (9 variants)
• Hyperthyroxinemia, dystransthyretinemic;Amyloidogenic transthyretin amyloidosis;Carpal tunnel syndrome 1 (9 variants)
• AMYLOIDOSIS, LEPTOMENINGEAL, TRANSTHYRETIN-RELATED (4 variants)
• Amyloidogenic transthyretin amyloidosis;Carpal tunnel syndrome 1;Hyperthyroxinemia, dystransthyretinemic (4 variants)
• Tip-toe gait (3 variants)
• TTR-related condition (3 variants)
• Carpal tunnel syndrome 1;Amyloidogenic transthyretin amyloidosis;Hyperthyroxinemia, dystransthyretinemic (3 variants)
• Inborn genetic diseases (2 variants)
• Carpal tunnel syndrome 1;Hyperthyroxinemia, dystransthyretinemic;Amyloidogenic transthyretin amyloidosis (2 variants)
• Hereditary amyloidosis (2 variants)
• Hyperthyroxinemia, dystransthyretinemic (2 variants)
• Anemia;Bone marrow hypocellularity;Pancytopenia (1 variants)
• Hereditary ATTR amyloidosis (1 variants)
• ATTRV122I amyloidosis (1 variants)
• Amyloid Cardiomyopathy, Transthyretin-related (1 variants)
• AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED, MODIFIER OF (1 variants)
• Heart failure (1 variants)
• Carpal tunnel syndrome (1 variants)
• Brugada syndrome (1 variants)
• TTR-related disorders (1 variants)
• Hypertrophic cardiomyopathy 1 (1 variants)
• Conduction disorder of the heart (1 variants)
• Amyloidogenic transthyretin amyloidosis;Hyperthyroxinemia, dystransthyretinemic;Carpal tunnel syndrome (1 variants)
• Primary familial hypertrophic cardiomyopathy (1 variants)
• TRANSTHYRETIN POLYMORPHISM (1 variants)
• Hypertrophic cardiomyopathy (1 variants)
• Amyloidosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TTR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				42	1	43
missense	39	54	74	3		170
nonsense			3			3
start loss						0
frameshift			6			6
inframe indel	1		5			6
splice donor/acceptor (+/-2bp)			7			7
splice region			8	9		17
non coding			5	23	6	34
Total	40	54	100	68	7

Highest pathogenic variant AF is 0.00467

Variants in TTR

This is a list of pathogenic ClinVar variants found in the TTR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
18-31591160-A-T		Familial amyloid neuropathy • Hyperthyroxinemia, dystransthyretinemic;Familial amyloid neuropathy;Carpal tunnel syndrome 1	Benign/Likely benign (Jan 29, 2024)
18-31591801-G-T		Familial amyloid neuropathy	Conflicting classifications of pathogenicity (Apr 27, 2017)
18-31591842-G-A		Familial amyloid neuropathy • Hyperthyroxinemia, dystransthyretinemic;Carpal tunnel syndrome 1;Familial amyloid neuropathy	Uncertain significance (May 19, 2022)
18-31591857-C-T		not specified	Likely benign (May 15, 2017)
18-31591888-C-T		Hyperthyroxinemia, dystransthyretinemic;Familial amyloid neuropathy;Carpal tunnel syndrome 1 • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Jul 08, 2021)
18-31591900-A-G		Cardiovascular phenotype	Conflicting classifications of pathogenicity (Aug 17, 2022)
18-31591902-G-C		Cardiovascular phenotype	Uncertain significance (Feb 10, 2020)
18-31591908-T-G		Familial amyloid neuropathy	Likely benign (Jul 14, 2023)
18-31591910-CTCA-C		Familial amyloid neuropathy • Hyperthyroxinemia, dystransthyretinemic;Familial amyloid neuropathy;Carpal tunnel syndrome 1	Uncertain significance (Nov 27, 2023)
18-31591911-T-C		Familial amyloid neuropathy • Cardiovascular phenotype	Likely benign (Nov 05, 2023)
18-31591910-C-CTCA		Familial amyloid neuropathy • Hyperthyroxinemia, dystransthyretinemic;Carpal tunnel syndrome 1;Familial amyloid neuropathy • Cardiovascular phenotype	Uncertain significance (Sep 23, 2023)
18-31591913-A-T		Familial amyloid neuropathy • Charcot-Marie-Tooth disease • Cardiovascular phenotype	Uncertain significance (Dec 06, 2023)
18-31591914-T-A		Familial amyloid neuropathy	Uncertain significance (Aug 04, 2021)
18-31591915-C-G		Familial amyloid neuropathy	Uncertain significance (Oct 20, 2021)
18-31591915-C-T		Familial amyloid neuropathy • Carpal tunnel syndrome 1;Hyperthyroxinemia, dystransthyretinemic;Familial amyloid neuropathy • Cardiovascular phenotype	Uncertain significance (Feb 10, 2023)
18-31591916-G-A		not specified • Cardiovascular phenotype • Familial amyloid neuropathy • Cardiomyopathy • Charcot-Marie-Tooth disease • TTR-related disorder	Conflicting classifications of pathogenicity (Jan 27, 2024)
18-31591923-C-T		Familial amyloid neuropathy	Likely benign (Jan 21, 2021)
18-31591926-C-T		Familial amyloid neuropathy • Cardiovascular phenotype	Benign/Likely benign (Feb 14, 2023)
18-31591927-C-T		Familial amyloid neuropathy	Uncertain significance (Dec 06, 2017)
18-31591936-G-T		Familial amyloid neuropathy • Cardiovascular phenotype	Uncertain significance (Aug 22, 2022)
18-31591937-C-A		Familial amyloid neuropathy	Uncertain significance (Dec 11, 2019)
18-31591937-C-T		Familial amyloid neuropathy	Uncertain significance (Feb 06, 2022)
18-31591939-G-A		Familial amyloid neuropathy • Familial amyloid neuropathy;Carpal tunnel syndrome 1;Hyperthyroxinemia, dystransthyretinemic	Uncertain significance (Oct 09, 2023)
18-31591942-C-T		Familial amyloid neuropathy • Familial amyloid neuropathy;Hyperthyroxinemia, dystransthyretinemic;Carpal tunnel syndrome 1	Benign/Likely benign (Nov 14, 2022)
18-31591947-A-G		Familial amyloid neuropathy	Likely benign (Nov 29, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TTR	protein_coding	protein_coding	ENST00000237014	4	7286

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.516	0.469	125741	0	3	125744	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.01	57	83.0	0.687	0.00000464	934
Missense in Polyphen		17	28.783	0.59064		343
Synonymous	0.433	30	33.2	0.904	0.00000190	312
Loss of Function	1.94	1	6.22	0.161	3.52e-7	69

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000264	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain. {ECO:0000269|PubMed:3714052}.
• Disease: DISEASE: Amyloidosis, transthyretin-related (AMYL-TTR) [MIM:105210]: A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor. {ECO:0000269|PubMed:10036587, ECO:0000269|PubMed:10071047, ECO:0000269|PubMed:10211412, ECO:0000269|PubMed:10436378, ECO:0000269|PubMed:10439117, ECO:0000269|PubMed:10611950, ECO:0000269|PubMed:10627135, ECO:0000269|PubMed:10694917, ECO:0000269|PubMed:10842705, ECO:0000269|PubMed:10842718, ECO:0000269|PubMed:10882995, ECO:0000269|PubMed:11243784, ECO:0000269|PubMed:11445644, ECO:0000269|PubMed:11866053, ECO:0000269|PubMed:12050338, ECO:0000269|PubMed:12403615, ECO:0000269|PubMed:12557757, ECO:0000269|PubMed:12771253, ECO:0000269|PubMed:1301926, ECO:0000269|PubMed:1351039, ECO:0000269|PubMed:1362222, ECO:0000269|PubMed:1436517, ECO:0000269|PubMed:1517749, ECO:0000269|PubMed:1520326, ECO:0000269|PubMed:1520336, ECO:0000269|PubMed:15214015, ECO:0000269|PubMed:15217993, ECO:0000269|PubMed:1544214, ECO:0000269|PubMed:15478468, ECO:0000269|PubMed:1570831, ECO:0000269|PubMed:15735344, ECO:0000269|PubMed:16185074, ECO:0000269|PubMed:1656975, ECO:0000269|PubMed:16627944, ECO:0000269|PubMed:1734866, ECO:0000269|PubMed:17453626, ECO:0000269|PubMed:17503405, ECO:0000269|PubMed:17577687, ECO:0000269|PubMed:17635579, ECO:0000269|PubMed:19167329, ECO:0000269|PubMed:1932142, ECO:0000269|PubMed:2046936, ECO:0000269|PubMed:2161654, ECO:0000269|PubMed:23317988, ECO:0000269|PubMed:2363717, ECO:0000269|PubMed:2891727, ECO:0000269|PubMed:3022108, ECO:0000269|PubMed:3135807, ECO:0000269|PubMed:3722385, ECO:0000269|PubMed:3818577, ECO:0000269|PubMed:6487335, ECO:0000269|PubMed:6583672, ECO:0000269|PubMed:6651852, ECO:0000269|PubMed:7655883, ECO:0000269|PubMed:7850982, ECO:0000269|PubMed:7910950, ECO:0000269|PubMed:7914929, ECO:0000269|PubMed:7923855, ECO:0000269|PubMed:8019560, ECO:0000269|PubMed:8038017, ECO:0000269|PubMed:8081397, ECO:0000269|PubMed:8095302, ECO:0000269|PubMed:8133316, ECO:0000269|PubMed:8257997, ECO:0000269|PubMed:8352764, ECO:0000269|PubMed:8382610, ECO:0000269|PubMed:8428915, ECO:0000269|PubMed:8579098, ECO:0000269|PubMed:8990019, ECO:0000269|PubMed:9066351, ECO:0000269|PubMed:9605286, ECO:0000269|PubMed:9733771, ECO:0000269|Ref.90}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperthyroxinemia, dystransthyretinemic (DTTRH) [MIM:145680]: A condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities. {ECO:0000269|PubMed:1979335}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Carpal tunnel syndrome 1 (CTS1) [MIM:115430]: A condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis. {ECO:0000269|PubMed:8309582}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Thyroid hormone synthesis - Homo sapiens (human);Signaling by GPCR;Neutrophil degranulation;Signal Transduction;Metabolism of fat-soluble vitamins;Extracellular matrix organization;Innate Immune System;Immune System;Metabolism;The canonical retinoid cycle in rods (twilight vision);Metabolism of vitamins and cofactors;Retinoid metabolism and transport;Non-integrin membrane-ECM interactions;G alpha (i) signalling events;Visual phototransduction;GPCR downstream signalling;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.845

Intolerance Scores

• loftool: 0.0557
• rvis_EVS: 0.5
• rvis_percentile_EVS: 79.89

Haploinsufficiency Scores

• pHI: 0.599
• hipred: N
• hipred_score: 0.457
• ghis: 0.431

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.869

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ttr
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: retinoid metabolic process;purine nucleobase metabolic process;regulation of signaling receptor activity;extracellular matrix organization;retinol metabolic process;neutrophil degranulation;cellular protein metabolic process;thyroid hormone transport
• Cellular component: extracellular region;extracellular space;protein-containing complex;azurophil granule lumen;extracellular exosome
• Molecular function: hormone activity;protein binding;identical protein binding;protein heterodimerization activity;thyroid hormone binding