TTR
transthyretin, the group of Gla domain containing
Basic information
Region (hg38): 18:31557009-31598833
Previous symbols: [ "PALB", "CTS1" ]
Links
Phenotypes
GenCC
Source:
- 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
- amyloidosis, hereditary systemic 1 (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Amyloidosis, hereditary, systemic 1; Hyperthyroxinemia, dystransthyretinemic | AD | Cardiovascular; Endocrine; Gastrointestinal; Neurologic | In Hereditary amyloidosis, surveillance for cardiovascular sequelae (which can include arrhythmias), and earlier treatment (eg, with pacemaker placement) 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; 37624911; 39213194 |
ClinVar
This is a list of variants' phenotypes submitted to
- Amyloidosis,_hereditary_systemic_1 (336 variants)
- Cardiovascular_phenotype (162 variants)
- not_provided (117 variants)
- not_specified (62 variants)
- Hyperthyroxinemia,_dystransthyretinemic (44 variants)
- Carpal_tunnel_syndrome_1 (42 variants)
- Cardiomyopathy (28 variants)
- Charcot-Marie-Tooth_disease (26 variants)
- TTR-related_disorder (11 variants)
- Tip-toe_gait (3 variants)
- Amyloidosis (3 variants)
- Hereditary_amyloidosis (2 variants)
- Carpal_tunnel_syndrome (2 variants)
- Hypertrophic_cardiomyopathy (1 variants)
- Conduction_disorder_of_the_heart (1 variants)
- ATTRV122I_amyloidosis (1 variants)
- Heart_failure (1 variants)
- EBV-positive_nodal_T-_and_NK-cell_lymphoma (1 variants)
- Primary_familial_hypertrophic_cardiomyopathy (1 variants)
- AMYLOIDOSIS,_HEREDITARY_SYSTEMIC_1,_MODIFIER_OF (1 variants)
- Brugada_syndrome (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. These statistics are base on transcript: NM_000000371.4. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 62 | 69 | ||||
| missense | 55 | 79 | 92 | 234 | ||
| nonsense | 5 | |||||
| start loss | 0 | |||||
| frameshift | 8 | |||||
| splice donor/acceptor (+/-2bp) | 6 | |||||
| Total | 55 | 79 | 113 | 69 | 6 |
Highest pathogenic variant AF is 0.000887811
Loading clinvar variants...
GnomAD
Source:
| 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:
- 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