ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.416C>T (p.Thr139Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(1); Benign(7); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000371.4(TTR):c.416C>T (p.Thr139Met)
Variation ID: 13434 Accession: VCV000013434.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31598647 (GRCh38) [ NCBI UCSC ] 18: 29178610 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jun 17, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.416C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Thr139Met missense NC_000018.10:g.31598647C>T NC_000018.9:g.29178610C>T NG_009490.1:g.11881C>T LRG_416:g.11881C>T LRG_416t1:c.416C>T LRG_416p1:p.Thr139Met P02766:p.Thr139Met - Protein change
- T139M
- Other names
- T119M
- p.T139M:ACG>ATG
- Canonical SPDI
- NC_000018.10:31598646:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
Exome Aggregation Consortium (ExAC) 0.00147
The Genome Aggregation Database (gnomAD), exomes 0.00151
Trans-Omics for Precision Medicine (TOPMed) 0.00170
The Genome Aggregation Database (gnomAD) 0.00177
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTR | - | - |
GRCh38 GRCh37 |
372 | 416 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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AMYLOIDOSIS, HEREDITARY SYSTEMIC 1, MODIFIER OF
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risk factor (1) |
no assertion criteria provided
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Sep 28, 2001 | RCV000014376.27 |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Sep 15, 2021 | RCV000036376.21 | |
Likely benign (1) |
criteria provided, single submitter
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May 8, 2018 | RCV000618448.12 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV000714134.46 | |
Benign (1) |
criteria provided, single submitter
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Jun 21, 2018 | RCV001170385.10 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000990084.19 | |
Likely benign (1) |
criteria provided, single submitter
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- | RCV001173303.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV003993656.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(May 22, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000169669.11
First in ClinVar: Jun 23, 2014 Last updated: May 29, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140875.1
First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020 |
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Benign
(Jun 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001332962.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Benign
(Dec 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000844811.3
First in ClinVar: Oct 20, 2018 Last updated: Sep 19, 2021 |
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Benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000554851.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Benign
(Nov 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605506.10
First in ClinVar: May 29, 2016 Last updated: Feb 20, 2024 |
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Likely pathogenic
(Sep 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperthyroxinemia, dystransthyretinemic
Affected status: yes
Allele origin:
germline
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Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV004809208.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
PS3,PS4_Moderate,PP4
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Benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001284998.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
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Likely benign
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336387.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
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Benign
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060029.7
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Thr139Met variant in TTR is classified as benign because it has been identified in 0.3% (351/129156) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this … (more)
The p.Thr139Met variant in TTR is classified as benign because it has been identified in 0.3% (351/129156) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this variant has been reported in both unaffected individuals as well as in individuals with asymptomatic euthyroid hyperthyroxinemia (Scrimshaw 1992, Alves 1997). Functional and clinical studies indicate that this variant may provide protective benefit against TTR amyloidosis by improving protein stability and reducing the propensity to form amyloidogenic aggregates (Quintas 1997, Almeida 2000, Hammarstrom 2001, Costa 2008, Palhano 2009, Borgault 2011). ACMG/AMP Criteria applied: BA1. (less)
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Likely benign
(May 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000735097.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001151528.23
First in ClinVar: Feb 03, 2020 Last updated: Jun 17, 2024 |
Comment:
TTR: BS1
Number of individuals with the variant: 6
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risk factor
(Sep 28, 2001)
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no assertion criteria provided
Method: literature only
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AMYLOIDOSIS, HEREDITARY SYSTEMIC 1, MODIFIER OF
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034625.2
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2024 |
Comment on evidence:
The substitution of methionine for threonine at codon 119 (T119M) influences the clinical outcome of met30 carriers with amyloidosis (176300.0001), with met119 exerting a protective … (more)
The substitution of methionine for threonine at codon 119 (T119M) influences the clinical outcome of met30 carriers with amyloidosis (176300.0001), with met119 exerting a protective effect. In a North American kindred of Swedish ancestry, Harrison et al. (1991) identified an apparently benign, electrophoretic variant of prealbumin, which they designated prealbumin Chicago. They identified a C-to-T mutation in exon 4 of the TTR gene which resulted in replacement of threonine by methionine at position 119 of the mature molecule (T119M). The variant was found incidentally in a girl with classic alpha-1-antitrypsin (AAT) deficiency (107400) and in her father during AAT phenotyping by an electrophoretic method. Five heterozygotes in 3 generations were studied. There was no evidence of amyloidosis in the family. Mean values of serum prealbumin and retinol binding protein levels were higher in the carriers than in normal relatives, but the difference was not statistically significant. The substitution at position 119 occurred in a CpG dinucleotide that may be a point mutation hotspot, as has been postulated for the methionine-30 and isoleucine-122 TTR mutations. Ii et al. (1992) also found this variant. Since thr119 is invariant in 5 mammalian species, it is presumably important to normal protein function. To determine the frequency of the variant, Ii et al. (1992) screened persons of northern- and western-European descent by means of a PASA (PCR amplification of specific alleles) assay. In all, they found 5 instances of the met119 allele in 1,666 genes, to give a frequency of 1/333. Clinical records, initial clinical interviews, and family history of these patients suggested a high frequency of early-onset venous insufficiency and perhaps mild renal dysfunction. Haplotype analysis suggested that the variant derived from a common ancestor. Ii et al. (1992) commented that although traditionally clinical research has sought to determine the molecular basis of clinical signs and symptoms, increasingly the process will be reversed, as structural protein variants are discovered. Scrimshaw et al. (1992) identified the same mutation, ACG-to-ATG at position 119, in 4 unrelated persons with euthyroid hyperthyroxinemia (145680). The mutation created a new NcoI restriction endonuclease cleavage site which permitted its detection by a rapid and simple assay based on PCR. Scrimshaw et al. (1992) concluded that although the thr119-to-met mutation was associated with increased binding of thyroxine, the hyperthyroxinemia in the patients who brought the variant to their attention had some other explanation because many persons with the variant had normal serum thyroxine concentrations. Alves et al. (1993) found another family with this mutation during a screening program for TTR mutations in the Portuguese FAP population. Cyanogen bromide peptide mapping and DNA RFLP analyses showed that the proband was a compound heterozygote for 2 TTR variants: his90-to-asn (176300.0010) and thr119-to-met, inherited from the father and mother, respectively. Neither the compound heterozygote nor his parents had symptoms of FAP. Alves et al. (1993) confirmed that TTR binding of T4 was increased in association with the met119 mutation. Coelho et al. (1996) found that compound heterozygotes of transthyretin met30 and met119 were protected from the devastating effects of familial amyloid polyneuropathy. The V30M mutation (176300.0001) is a prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas the thr119-to-met mutation (T119M) on the second TTR allele protects V30M carriers from disease. Hammarstrom et al. (2001) demonstrated that the incorporation of 1 or more T119M TTR subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation, which is required for amyloid formation. Hammarstrom et al. (2001) concluded that their findings provided a molecular explanation for intragenic trans-suppression of amyloidosis. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969591.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Diagnosis of genetic amyloidosis through the analysis of transthyretin gene mutation using high-resolution melting. | Lahuerta C | International journal of cardiology | 2020 | PMID: 31740141 |
Cellular secretion and cytotoxicity of transthyretin mutant proteins underlie late-onset amyloidosis and neurodegeneration. | Ibrahim RB | Cellular and molecular life sciences : CMLS | 2020 | PMID: 31728576 |
Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. | Rowczenio D | Human mutation | 2019 | PMID: 30328212 |
Structure of Monomeric Transthyretin Carrying the Clinically Important T119M Mutation. | Kim JH | Angewandte Chemie (International ed. in English) | 2016 | PMID: 27885756 |
Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. | Sassi C | PloS one | 2016 | PMID: 27249223 |
A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis. | Marcoux J | EMBO molecular medicine | 2015 | PMID: 26286619 |
Whole-genome sequence-based analysis of thyroid function. | Taylor PN | Nature communications | 2015 | PMID: 25743335 |
Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy. | Hornstrup LS | Arteriosclerosis, thrombosis, and vascular biology | 2013 | PMID: 23580146 |
Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs. | Bourgault S | Biochemical and biophysical research communications | 2011 | PMID: 21557933 |
Trapping the monomer of a non-amyloidogenic variant of transthyretin: exploring its possible use as a therapeutic strategy against transthyretin amyloidogenic diseases. | Palhano FL | The Journal of biological chemistry | 2009 | PMID: 18984591 |
Transthyretin binding to A-Beta peptide--impact on A-Beta fibrillogenesis and toxicity. | Costa R | FEBS letters | 2008 | PMID: 18295603 |
Different disease-causing mutations in transthyretin trigger the same conformational conversion. | Steward RE | Protein engineering, design & selection : PEDS | 2008 | PMID: 18276611 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
Tabulation of human transthyretin (TTR) variants, 2003. | Connors LH | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 14640030 |
Trans-suppression of misfolding in an amyloid disease. | Hammarström P | Science (New York, N.Y.) | 2001 | PMID: 11577236 |
Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution. | Sebastião MP | Journal of molecular biology | 2001 | PMID: 11243784 |
Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M. | Almeida MR | Biochemical and biophysical research communications | 2000 | PMID: 10772944 |
The amyloidogenic potential of transthyretin variants correlates with their tendency to aggregate in solution. | Quintas A | FEBS letters | 1997 | PMID: 9428731 |
Comparative stability and clearance of [Met30]transthyretin and [Met119]transthyretin. | Longo Alves I | European journal of biochemistry | 1997 | PMID: 9395311 |
Screening and biochemical characterization of transthyretin variants in the Portuguese population. | Alves IL | Human mutation | 1997 | PMID: 9090525 |
Thyroxine binding by human transthyretin variants: mutations at position 119, but not position 54, increase thyroxine binding affinity. | Curtis AJ | The Journal of clinical endocrinology and metabolism | 1994 | PMID: 7906282 |
Thyroxine binding in a TTR Met 119 kindred. | Alves IL | The Journal of clinical endocrinology and metabolism | 1993 | PMID: 8102146 |
From molecular variant to disease: initial steps in evaluating the association of transthyretin M119 with disease. | Ii S | American journal of human genetics | 1992 | PMID: 1729893 |
A novel variant of transthyretin (prealbumin), Thr119 to Met, associated with increased thyroxine binding. | Scrimshaw BJ | Thyroid : official journal of the American Thyroid Association | 1992 | PMID: 1356051 |
Biochemical and clinical characterization of prealbuminCHICAGO: an apparently benign variant of serum prealbumin (transthyretin) discovered with high-resolution two-dimensional electrophoresis. | Harrison HH | American journal of medical genetics | 1991 | PMID: 1877623 |
Coelho, T., Chorao, R., Sousa, A., Alves, I. L., Torres, M. F., Saraiva, M. J. M. Compound heterozygotes of transthyretin Met 30 and transthyretin Met 119 are protected from the devastating effects of familial amyloid polyneuropathy. (Abstract) Neuromusc. Disord. 6 (suppl. 1): S20-only, 1996. | - | - | - | - |
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Text-mined citations for rs28933981 ...
HelpRecord last updated Jun 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.