ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.293A>T (p.Tyr98Phe)
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.293A>T (p.Tyr98Phe)
Variation ID: 1294424 Accession: VCV001294424.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31595212 (GRCh38) [ NCBI UCSC ] 18: 29175175 (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 Sep 29, 2021 Feb 14, 2024 Sep 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.293A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Tyr98Phe missense NC_000018.10:g.31595212A>T NC_000018.9:g.29175175A>T NG_009490.1:g.8446A>T LRG_416:g.8446A>T LRG_416t1:c.293A>T - Protein change
- Y98F
- Other names
- p.Tyr78Phe
- Canonical SPDI
- NC_000018.10:31595211:A: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 | 413 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Sep 23, 2022 | RCV001718568.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 1, 2021 | RCV002440842.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2023 | RCV003329411.1 |
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
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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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Pathogenic
(Jul 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Breda Genetics srl
Accession: SCV001943368.1
First in ClinVar: Sep 29, 2021 Last updated: Sep 29, 2021 |
Comment:
The variant c.293A>T (p.Tyr78Phe) in the TTR gene, also known as c.293A>T (p.Tyr98Phe) is reported as pathogenic in the Global Variome shared LOVD v.3.0 database. … (more)
The variant c.293A>T (p.Tyr78Phe) in the TTR gene, also known as c.293A>T (p.Tyr98Phe) is reported as pathogenic in the Global Variome shared LOVD v.3.0 database. There is no frequency information in the gnomAD database. The nucleotide position is highly conserved in 35 mammal species (GERP RS: 5.54). This variant was first reported as pathogenic by Magy et al. (2003) in a 78-year-old patient of Italian origin with a 5-year history of lower limbs peripheral polyneuropathy, and who was operated on for carpal tunnel syndrome (PMID:12762139). It was then reported by Riboldi et al. (2011) in a 63-year-old patient with a suspicion of motor neuron disease. The patient presented with distal limb paralysis, atrophy, carpal tunnel and other systemic multiorgan defects such as renal malfunction, cardiac fibrillation and cataracts (PMID:21490715). Curiously, as argued by Tini et al. (2018), although the variant does not have a frequency in population databases, it seems to have a predominantly Italian geographical location (4 patients have been reported in the literature, two of which of Italian origin and two deriving from Italian studies and presumably Italian) (PMID:30604309 ). (less)
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Likely pathogenic
(May 01, 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: SCV002747819.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.Y98F variant (also known as c.293A>T), located in coding exon 3 of the TTR gene, results from an A to T substitution at nucleotide … (more)
The p.Y98F variant (also known as c.293A>T), located in coding exon 3 of the TTR gene, results from an A to T substitution at nucleotide position 293. The tyrosine at codon 98 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration, also known as p.Y78F by legacy nomenclature, has been reported in the literature in several individuals with transthyretin (TTR) amyloidosis (Magy N et al. Amyloid, 2003 Mar;10:29-33; Riboldi G et al. Case Rep Neurol, 2011 Feb;3:62-8; Rapezzi C et al. Eur Heart J, 2013 Feb;34:520-8; Luigetti M et al. Brain Sci, 2020 Oct;10:[Epub ahead of print]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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
(Sep 22, 2023)
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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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GeneDx
Accession: SCV004036908.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
Functional studies demonstrate altered monomer stability and increased amyloid formation; this variant is commonly used to test the effectiveness of potential anti-amyloidogenesis compounds (Redondo et … (more)
Functional studies demonstrate altered monomer stability and increased amyloid formation; this variant is commonly used to test the effectiveness of potential anti-amyloidogenesis compounds (Redondo et al., 2000; Almeida et al., 2004; Terazaki et al., 2006; Altland et al., 2007; Ferreira et al., 2009; Dess et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Y78F); This variant is associated with the following publications: (PMID: 16357867, 18295603, 32397334, 18776590, 11090287, 21740906, 19861125, 15080795, 22745357, 12762139, 21490715, 30350904, 11545098, 30604309, 14640030, 25604431, 33114611, 34410494, 17503405) (less)
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Pathogenic
(Sep 23, 2022)
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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: SCV002244571.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TTR function (PMID: 17503405). 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. ClinVar contains an entry for this variant (Variation ID: 1294424). This variant is also known as p.Tyr78Phe. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 12762139, 21490715, 22745357, 30604309). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 98 of the TTR protein (p.Tyr98Phe). (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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hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers. | Luigetti M | Brain sciences | 2020 | PMID: 33114611 |
Amyloid Cardiomyopathy in the Rare Transthyretin Tyr78Phe Mutation. | Tini G | Journal of cardiovascular translational research | 2019 | PMID: 30604309 |
Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. | Rapezzi C | European heart journal | 2013 | PMID: 22745357 |
Tyr78Phe Transthyretin Mutation with Predominant Motor Neuropathy as the Initial Presentation. | Riboldi G | Case reports in neurology | 2011 | PMID: 21490715 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. | Magy N | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 12762139 |
Text-mined citations for rs958191819 ...
HelpRecord last updated Apr 15, 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.