ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)
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_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)
Variation ID: 217016 Accession: VCV000217016.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30688395 (GRCh38) [ NCBI UCSC ] 3: 30729887 (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 11, 2015 Feb 20, 2024 May 21, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1408T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Tyr470Asp missense NM_001024847.3:c.1483T>G NP_001020018.1:p.Tyr495Asp missense NM_001407126.1:c.1591T>G NP_001394055.1:p.Tyr531Asp missense NM_001407127.1:c.1516T>G NP_001394056.1:p.Tyr506Asp missense NM_001407128.1:c.1435T>G NP_001394057.1:p.Tyr479Asp missense NM_001407129.1:c.1411T>G NP_001394058.1:p.Tyr471Asp missense NM_001407130.1:c.1405T>G NP_001394059.1:p.Tyr469Asp missense NM_001407132.1:c.1303T>G NP_001394061.1:p.Tyr435Asp missense NM_001407133.1:c.1303T>G NP_001394062.1:p.Tyr435Asp missense NM_001407134.1:c.1303T>G NP_001394063.1:p.Tyr435Asp missense NM_001407135.1:c.1303T>G NP_001394064.1:p.Tyr435Asp missense NM_001407136.1:c.1303T>G NP_001394065.1:p.Tyr435Asp missense NM_001407137.1:c.1123T>G NP_001394066.1:p.Tyr375Asp missense NM_001407138.1:c.1048T>G NP_001394067.1:p.Tyr350Asp missense NM_001407139.1:c.538T>G NP_001394068.1:p.Tyr180Asp missense NC_000003.12:g.30688395T>G NC_000003.11:g.30729887T>G NG_007490.1:g.86894T>G LRG_779:g.86894T>G LRG_779t1:c.1483T>G LRG_779p1:p.Tyr495Asp LRG_779t2:c.1408T>G LRG_779p2:p.Tyr470Asp - Protein change
- Y470D, Y495D, Y180D, Y350D, Y471D, Y506D, Y435D, Y469D, Y375D, Y479D, Y531D
- Other names
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- Canonical SPDI
- NC_000003.12:30688394:T:G
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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.
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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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TGFBR2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1131 | 1156 |
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Apr 30, 2013 | RCV000197170.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 21, 2022 | RCV002310796.10 |
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
(Apr 30, 2013)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255488.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 40-49 years
Sex: female
Ethnicity/Population group: European Caucasian
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(Feb 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000318668.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.Y470D pathogenic mutation (also known as c.1408T>G), located in coding exon 6 of the TGFBR2 gene, results from a T to G substitution at … (more)
The p.Y470D pathogenic mutation (also known as c.1408T>G), located in coding exon 6 of the TGFBR2 gene, results from a T to G substitution at nucleotide position 1408. The tyrosine at codon 470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been previously reported in an individual with suspected Marfan or Loeys-Dietz syndrome (Lee H et al. JAMA 2014 Nov; 312(18):1880-7) and segregates with disease in one family tested in our laboratory (Ambry internal data). In a study of patients with aortic aneurysms/dissections, an alteration of the same codon, p.Y470S (c.1409A>C), in the protein kinase domain was detected in one patient (Waldmüller S et al. Eur J Cardiothorac Surg. 2007;31(6):970-5). Phosphorylation of p.Y470 has been shown to be important for TGFBR2 function (Chen X et al. J. Clin. Invest. 2014 Aug; 124(8):3295-310), and TGFBR2 is inactivated in a cancer cell line with p.Y470D as well as a second TGFBR2 substitution (p.K52T; Grady WM et al. Cancer Res. 1999 Jan; 59(2):320-4). Based on the supporting evidence, p.Y470D is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003482752.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr470 amino acid residue in TGFBR2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr470 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26848186, 27879313; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 217016). This missense change has been observed in individuals with clinical features of Loeys-Dietz syndrome (PMID: 25326637; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 470 of the TGFBR2 protein (p.Tyr470Asp). (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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International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). | Jondeau G | Circulation. Cardiovascular genetics | 2016 | PMID: 27879313 |
Heterogeneity of aortic disease severity in patients with Loeys-Dietz syndrome. | Teixidó-Tura G | Heart (British Cardiac Society) | 2016 | PMID: 26848186 |
Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling. | Chen X | The Journal of clinical investigation | 2014 | PMID: 24983314 |
Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation? | Waldmüller S | European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery | 2007 | PMID: 17418587 |
Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. | Grady WM | Cancer research | 1999 | PMID: 9927040 |
Text-mined citations for rs863224935 ...
HelpRecord last updated Apr 20, 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.