ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1657T>A (p.Ser553Thr)
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.
Uncertain significance(1); Benign(8); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003242.6(TGFBR2):c.1657T>A (p.Ser553Thr)
Variation ID: 161394 Accession: VCV000161394.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30691552 (GRCh38) [ NCBI UCSC ] 3: 30733044 (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 Dec 7, 2014 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1657T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Ser553Thr missense NM_001024847.3:c.1732T>A NP_001020018.1:p.Ser578Thr missense NM_001407126.1:c.1840T>A NP_001394055.1:p.Ser614Thr missense NM_001407127.1:c.1765T>A NP_001394056.1:p.Ser589Thr missense NM_001407128.1:c.1684T>A NP_001394057.1:p.Ser562Thr missense NM_001407129.1:c.1660T>A NP_001394058.1:p.Ser554Thr missense NM_001407130.1:c.1654T>A NP_001394059.1:p.Ser552Thr missense NM_001407132.1:c.1552T>A NP_001394061.1:p.Ser518Thr missense NM_001407133.1:c.1552T>A NP_001394062.1:p.Ser518Thr missense NM_001407134.1:c.1552T>A NP_001394063.1:p.Ser518Thr missense NM_001407135.1:c.1552T>A NP_001394064.1:p.Ser518Thr missense NM_001407136.1:c.1552T>A NP_001394065.1:p.Ser518Thr missense NM_001407137.1:c.1372T>A NP_001394066.1:p.Ser458Thr missense NM_001407138.1:c.1297T>A NP_001394067.1:p.Ser433Thr missense NM_001407139.1:c.787T>A NP_001394068.1:p.Ser263Thr missense NC_000003.12:g.30691552T>A NC_000003.11:g.30733044T>A NG_007490.1:g.90051T>A LRG_779:g.90051T>A LRG_779t1:c.1732T>A LRG_779p1:p.Ser578Thr LRG_779t2:c.1657T>A LRG_779p2:p.Ser553Thr - Protein change
- S578T, S553T, S554T, S433T, S458T, S518T, S552T, S562T, S589T, S614T, S263T
- Other names
- p.S553T:TCG>ACG
- Canonical SPDI
- NC_000003.12:30691551:T:A
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00179
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00138
Exome Aggregation Consortium (ExAC) 0.00140
Trans-Omics for Precision Medicine (TOPMed) 0.00114
The Genome Aggregation Database (gnomAD) 0.00115
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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TGFBR2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1131 | 1156 |
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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Likely benign (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148891.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 22, 2017 | RCV000152014.21 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 16, 2015 | RCV000239196.12 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000241715.28 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000337404.14 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000587520.17 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 1, 2018 | RCV000680614.9 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001094793.12 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 21, 2021 | RCV002277295.10 | |
Benign (1) |
criteria provided, single submitter
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Oct 5, 2020 | RCV003935259.1 |
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
(Apr 17, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698197.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The TGFBR2 c.1657T>A (p.Ser553Thr) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome. This variant … (more)
Variant summary: The TGFBR2 c.1657T>A (p.Ser553Thr) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome. This variant was found in 170/121354 control chromosomes (2 homozygotes) at a frequency of 0.0014009, which is approximately 1121 times the estimated maximal expected allele frequency of a pathogenic TGFBR2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant with conflicting classifications "uncertain significance" or "likely benign." However, it needs to be noted that many databases/clinical diagnostic laboratories that classified the variant as "uncertain significance" were performed before ExAC data was availalbe. In addition, ClinVar-Partners does state that the variant did not segregate with disease in one family. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. (less)
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Benign
(Nov 22, 2017)
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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: SCV000250957.8
First in ClinVar: Oct 11, 2015 Last updated: Apr 09, 2018 |
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
(Jun 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Connective tissue disorder
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000808044.1
First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018 |
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Benign
(Dec 09, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000703465.2
First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Mar 15, 2018)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000910746.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Jan 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000200582.5
First in ClinVar: Jan 30, 2015 Last updated: Apr 09, 2018 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 3
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136358.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Oct 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002566159.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Benign
(Apr 06, 2016)
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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: SCV000318116.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Likely benign
(Nov 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000296974.3
First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022 |
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Likely benign
(Jul 22, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838138.2
First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024 |
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Benign
(Feb 01, 2024)
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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: SCV000559155.8
First in ClinVar: Dec 06, 2016 Last updated: Feb 28, 2024 |
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Benign
(Oct 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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TGFBR2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004747727.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Thoracic Aortic Aneurysms and Aortic Dissections
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000442905.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Marfan Syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000442904.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000442906.3
First in ClinVar: Dec 06, 2016 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Mar 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: SCV002821170.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
TGFBR2: BS1
Number of individuals with the variant: 32
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Likely benign
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Aortic aneurysm, thoracic
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190637.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 |
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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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Aortic dilation, genetic testing, and associated diagnoses. | Zarate YA | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26133393 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. | Carmi S | Nature communications | 2014 | PMID: 25203624 |
The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). | Lerner-Ellis JP | Molecular genetics and metabolism | 2014 | PMID: 24793577 |
Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. | Stheneur C | Human mutation | 2008 | PMID: 18781618 |
Recent progress in genetics of Marfan syndrome and Marfan-associated disorders. | Mizuguchi T | Journal of human genetics | 2007 | PMID: 17061023 |
Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. | Mátyás G | Human mutation | 2006 | PMID: 16791849 |
Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region. | Wieser R | Molecular and cellular biology | 1993 | PMID: 8246946 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TGFBR2 | - | - | - | - |
Text-mined citations for rs112215250 ...
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.