ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter)
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.1483C>T (p.Arg495Ter)
Variation ID: 12519 Accession: VCV000012519.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30688470 (GRCh38) [ NCBI UCSC ] 3: 30729962 (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 Feb 6, 2015 Feb 20, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1483C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Arg495Ter nonsense NM_001024847.3:c.1558C>T NP_001020018.1:p.Arg520Ter nonsense NM_001407126.1:c.1666C>T NP_001394055.1:p.Arg556Ter nonsense NM_001407127.1:c.1591C>T NP_001394056.1:p.Arg531Ter nonsense NM_001407128.1:c.1510C>T NP_001394057.1:p.Arg504Ter nonsense NM_001407129.1:c.1486C>T NP_001394058.1:p.Arg496Ter nonsense NM_001407130.1:c.1480C>T NP_001394059.1:p.Arg494Ter nonsense NM_001407132.1:c.1378C>T NP_001394061.1:p.Arg460Ter nonsense NM_001407133.1:c.1378C>T NP_001394062.1:p.Arg460Ter nonsense NM_001407134.1:c.1378C>T NP_001394063.1:p.Arg460Ter nonsense NM_001407135.1:c.1378C>T NP_001394064.1:p.Arg460Ter nonsense NM_001407136.1:c.1378C>T NP_001394065.1:p.Arg460Ter nonsense NM_001407137.1:c.1198C>T NP_001394066.1:p.Arg400Ter nonsense NM_001407138.1:c.1123C>T NP_001394067.1:p.Arg375Ter nonsense NM_001407139.1:c.613C>T NP_001394068.1:p.Arg205Ter nonsense NC_000003.12:g.30688470C>T NC_000003.11:g.30729962C>T NG_007490.1:g.86969C>T LRG_779:g.86969C>T LRG_779t1:c.1558C>T LRG_779p1:p.Arg520Ter LRG_779t2:c.1483C>T LRG_779p2:p.Arg495Ter - Protein change
- R495*, R520*, R205*, R556*, R400*, R375*, R504*, R531*, R460*, R494*, R496*
- Other names
- p.R495*:CGA>TGA
- Canonical SPDI
- NC_000003.12:30688469: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.
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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
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
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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
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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) |
no assertion criteria provided
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Aug 24, 2006 | RCV000013344.25 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 30, 2018 | RCV000157519.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2022 | RCV000195964.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000253575.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763512.3 |
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
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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
(Jan 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918308.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: TGFBR2 c.1483C>T (p.Arg495X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TGFBR2 c.1483C>T (p.Arg495X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245910 control chromosomes. The c.1483C>T variant has been reported in the literature in multiple individuals affected with Loeys-Dietz Syndrome, including segregation with disease in a family (Togashi_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, where an increase in intracellular collagen was observed in patient fibroblasts (Barnett_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, each of which classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Malignant tumor of esophagus
Loeys-Dietz syndrome 2 Colorectal cancer, hereditary nonpolyposis, type 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894313.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jun 01, 2022)
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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: SCV000250967.16
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect by causing intracellular accumulation of collagen type I … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect by causing intracellular accumulation of collagen type I in patient-derived cultured fibroblasts (Barnett et al., 2011); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 16928994, 18084123, 22113417, 17652900, 33059708, 34150014, 21267002, 26582918, 33084842) (less)
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Pathogenic
(May 15, 2023)
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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: SCV000319544.5
First in ClinVar: Oct 02, 2016 Last updated: Jul 08, 2023 |
Comment:
The p.R495* pathogenic mutation (also known as c.1483C>T), located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at … (more)
The p.R495* pathogenic mutation (also known as c.1483C>T), located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1483. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration occurs at the 3' terminus of theTGFBR2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.8% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in several individuals and families with a diagnosis of Loeys-Dietz syndrome (Loeys et al. N Engl J Med. 2006;355(8):788-98; Togashi et al. Intern Med. 2007;46(24):1995-2000; Yang et al. J Hum Genet. 2012;57:52-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 11, 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: SCV000658821.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg495*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg495*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the TGFBR2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Loeys-Dietz syndrome (PMID: 16928994, 17652900, 18084123, 22113417). ClinVar contains an entry for this variant (Variation ID: 12519). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 24, 2006)
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no assertion criteria provided
Method: literature only
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LOEYS-DIETZ SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033591.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Loeys et al. (2006) pictured a patient with Loeys-Dietz syndrome (LDS2; 610168) who carried a heterozygous nonsense mutation, arg495 to stop (R495X), in the TGFBR2 … (more)
Loeys et al. (2006) pictured a patient with Loeys-Dietz syndrome (LDS2; 610168) who carried a heterozygous nonsense mutation, arg495 to stop (R495X), in the TGFBR2 gene. The man showed hypertelorism and bifid uvula. Immunostaining of aortic tissue revealed increased nuclear accumulation of phosphorylated Smad2 (601366) and levels of expression of connective-tissue growth factor (CTGF; 121009), both indicative of increased TGF-beta signaling. (less)
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Likely pathogenic
(Jul 21, 2014)
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no assertion criteria provided
Method: clinical testing
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Loeys-Dietz syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000207264.1
First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 |
Number of individuals with the variant: 1
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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 |
Clinical features and genetic analysis of Korean patients with Loeys-Dietz syndrome. | Yang JH | Journal of human genetics | 2012 | PMID: 22113417 |
Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? | Barnett CP | European journal of human genetics : EJHG | 2011 | PMID: 21267002 |
A new locus-specific database (LSDB) for mutations in the TGFBR2 gene: UMD-TGFBR2. | Frederic MY | Human mutation | 2008 | PMID: 17935258 |
A Japanese family of typical Loeys-Dietz syndrome with a TGFBR2 mutation. | Togashi Y | Internal medicine (Tokyo, Japan) | 2007 | PMID: 18084123 |
Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factor-beta receptor genes. | Akutsu K | Circulation journal : official journal of the Japanese Circulation Society | 2007 | PMID: 17652900 |
Aneurysm syndromes caused by mutations in the TGF-beta receptor. | Loeys BL | The New England journal of medicine | 2006 | PMID: 16928994 |
Text-mined citations for rs104893819 ...
HelpRecord last updated Feb 28, 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.