ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.239C>T (p.Thr80Ile)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000371.4(TTR):c.239C>T (p.Thr80Ile)
Variation ID: 577420 Accession: VCV000577420.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31595158 (GRCh38) [ NCBI UCSC ] 18: 29175121 (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 Oct 10, 2018 Feb 14, 2024 Jan 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.239C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Thr80Ile missense NC_000018.10:g.31595158C>T NC_000018.9:g.29175121C>T NG_009490.1:g.8392C>T LRG_416:g.8392C>T LRG_416t1:c.239C>T LRG_416p1:p.Thr80Ile - Protein change
- T80I
- Other names
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- Canonical SPDI
- NC_000018.10:31595157: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
369 | 416 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (1) |
criteria provided, single submitter
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Jan 20, 2024 | RCV000700173.17 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2021 | RCV000756862.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2021 | RCV002458280.8 |
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
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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
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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
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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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Likely pathogenic
(Jan 21, 2018)
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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: SCV000884820.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The TTR c.239C>T; p.Thr80Ile variant is not reported in the literature and is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome … (more)
The TTR c.239C>T; p.Thr80Ile variant is not reported in the literature and is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. A different missense variant at codon 80 (Thr80Ala) has been reported in multiple unrelated patients with familial amyloidotic polyneuropathy (FAP) (Wallace 1986, Sattianayagam 2012) and is frequently associated with cardiac amyloidosis. Both p.Thr80Ala and p.Thr80Ile substitute the native uncharged polar residue with a nonpolar residue. The threonine at codon 80 is moderately conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging. Based on the above information, this variant is considered likely pathogenic. References: Wallace M et al. Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest. 1986 Jul; 78(1): 6–12. Sattianayagam P et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012 May;33(9):1120-7. (less)
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Likely pathogenic
(Sep 11, 2021)
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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: SCV002738512.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.T80I variant (also known as c.239C>T), located in coding exon 3 of the TTR gene, results from a C to T substitution at nucleotide … (more)
The p.T80I variant (also known as c.239C>T), located in coding exon 3 of the TTR gene, results from a C to T substitution at nucleotide position 239. The threonine at codon 80 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in multiple patients with transthyretin (ATTR) amyloidosis (Ambry internal data; Invitae pers comm). This variant was also described in a Saudi exome cohort; however, clinical details were limited (Abouelhoda M et al. Hum Genomics, 2021 Aug;15:52). An alternate amino acid substitution at this position, p.T80A (historically described as p.T60A), has been detected in numerous individuals with ATTR amyloidosis and is associated with cardiac symptoms (Wallace MR et al. J. Clin. Invest., 1986 Jul;78:6-12; Zeldenrust SR. Amyloid, 2012 Jun;19 Suppl 1:22-4; Ihse E et al. Amyloid, 2013 Sep;20:142-50; Swiecicki PL et al. Amyloid, 2015 May;22:123-31). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV002771674.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(Jan 20, 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: SCV000828918.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 80 of the TTR protein (p.Thr80Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 80 of the TTR protein (p.Thr80Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (Invitae). ClinVar contains an entry for this variant (Variation ID: 577420). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. This variant disrupts the p.Thr80 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 3722385, 12050338, 15820680, 21992998, 25997029, 26017327). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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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Established and candidate transthyretin amyloidosis variants identified in the Saudi population by data mining. | Abouelhoda M | Human genomics | 2021 | PMID: 34380564 |
Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. | Swiecicki PL | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2015 | PMID: 26017327 |
Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. | Fontana M | Radiology | 2015 | PMID: 25997029 |
Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. | Sattianayagam PT | European heart journal | 2012 | PMID: 21992998 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. | Lachmann HJ | The New England journal of medicine | 2002 | PMID: 12050338 |
Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. | Wallace MR | The Journal of clinical investigation | 1986 | PMID: 3722385 |
Text-mined citations for rs1254341785 ...
HelpRecord last updated Mar 23, 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.