ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1489C>T (p.Arg497Ter)
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.1489C>T (p.Arg497Ter)
Variation ID: 213934 Accession: VCV000213934.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30688476 (GRCh38) [ NCBI UCSC ] 3: 30729968 (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 14, 2024 Aug 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1489C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Arg497Ter nonsense NM_001024847.3:c.1564C>T NP_001020018.1:p.Arg522Ter nonsense NM_001407126.1:c.1672C>T NP_001394055.1:p.Arg558Ter nonsense NM_001407127.1:c.1597C>T NP_001394056.1:p.Arg533Ter nonsense NM_001407128.1:c.1516C>T NP_001394057.1:p.Arg506Ter nonsense NM_001407129.1:c.1492C>T NP_001394058.1:p.Arg498Ter nonsense NM_001407130.1:c.1486C>T NP_001394059.1:p.Arg496Ter nonsense NM_001407132.1:c.1384C>T NP_001394061.1:p.Arg462Ter nonsense NM_001407133.1:c.1384C>T NP_001394062.1:p.Arg462Ter nonsense NM_001407134.1:c.1384C>T NP_001394063.1:p.Arg462Ter nonsense NM_001407135.1:c.1384C>T NP_001394064.1:p.Arg462Ter nonsense NM_001407136.1:c.1384C>T NP_001394065.1:p.Arg462Ter nonsense NM_001407137.1:c.1204C>T NP_001394066.1:p.Arg402Ter nonsense NM_001407138.1:c.1129C>T NP_001394067.1:p.Arg377Ter nonsense NM_001407139.1:c.619C>T NP_001394068.1:p.Arg207Ter nonsense NC_000003.12:g.30688476C>T NC_000003.11:g.30729968C>T NG_007490.1:g.86975C>T LRG_779:g.86975C>T LRG_779t1:c.1564C>T LRG_779p1:p.Arg522Ter LRG_779t2:c.1489C>T LRG_779p2:p.Arg497Ter - Protein change
- R497*, R522*, R207*, R498*, R462*, R496*, R506*, R377*, R402*, R533*, R558*
- Other names
- p.R497*:CGA>TGA
- Canonical SPDI
- NC_000003.12:30688475: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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2023 | RCV000199072.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2022 | RCV000244033.7 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 30, 2016 | RCV000490801.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2018 | RCV000680613.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 26, 2020 | RCV001449740.5 |
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
(Dec 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 2
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740527.1
First in ClinVar: Jun 18, 2017 Last updated: Jun 18, 2017 |
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Pathogenic
(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: SCV000808043.1
First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018 |
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Pathogenic
(May 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653011.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
The p.Arg497X variant in TGFBR2 has been previously reported in 1 individual with Loeys-Dietz syndrome (LDS) and segregated with disease in at least 6 affected … (more)
The p.Arg497X variant in TGFBR2 has been previously reported in 1 individual with Loeys-Dietz syndrome (LDS) and segregated with disease in at least 6 affected relatives (Tooley 2017). It has also been reported as a de novo occurrence in 1 individual with clinical features of LDS, though it was not clear if maternity and paternity were confirmed (Yang 2012). Additionally, this variant has also been reported in 2 individuals with incomplete Marfan syndrome (Singh et al. 2006, Stheneur et al. 2008). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 213934) and is absent from large population studies. This nonsense variant leads to a premature termination codon at position 497. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 13% of the coding region, with about 72 amino acids removed. Several truncating variants located downstream of the p.Arg497X variant have been described in individuals with TGFBR2-associated disorders (Stheneur 2008, LMM unpublished data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LDS. ACMG/AMP criteria applied: PM2, PVS1_strong, PP1_Moderate, PM6. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 14, 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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Ambry Genetics
Accession: SCV000319476.4
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.R497* pathogenic mutation (also known as c.1489C>T) located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at … (more)
The p.R497* pathogenic mutation (also known as c.1489C>T) located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1489. This changes the amino acid from an arginine to a stop codon within coding exon 6. This stop codon occurs at the 3' terminus of TGFBR2 and is not expected to trigger nonsense-mediated decay. However, this variant eliminates the last 71 amino acids, including 48 amino acids from the C-terminal end of the protein kinase domain. This alteration has been detected in patients from Loeys-Dietz syndrome (LDS), Marfan syndrome-like, and thoracic aortic aneurysm and dissection (TAAD) cohorts in patients reported to have TAAD and other features consistent with LDS (Singh et al. Hum Mutat. 2006;27(8):770-7; Stheneur C et al. Hum Mutat.2008;29(11):E84-95; Jondeau G et al. Circ Cardiovasc Genet. 2016;9(6):548-558; Weerakkody R et al. Genet. Med. 2018 [Epub ahead of print]). In addition, this mutation has been reported to segregate with disease features in families (Cauldwell M et al. Int J Cardiol. 2016;214:491-2; Tooley MJ et al. Clin Dysmorphol. 2017;26(2):91-94). Multiple nonsense and missense alterations in the C-terminal end of the kinase domain have been associated with LDS or related phenotypes (Loeys BL et al. N Engl J Med. 2006;355:788-98; Stheneur C et al. Hum Mutat. 2008;29:E284-95; Horbelt D et al. J Cell Sci. 2010;123:4340-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 11, 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: SCV000250949.17
First in ClinVar: Oct 11, 2015 Last updated: Aug 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 71 amino acids are … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 71 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 18781618, 22113417, 25525159, 17061023, 19996017, 28225382, 29543232, 16799921, 27879313, 27100340) (less)
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Pathogenic
(Dec 08, 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: SCV000776690.4
First in ClinVar: Apr 09, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TGFBR2 protein in which other variant(s) (p.Gln511*) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TGFBR2 protein in which other variant(s) (p.Gln511*) have been determined to be pathogenic (PMID: 15235604, 18781618). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 213934). This variant is also known as p.R522X. This premature translational stop signal has been observed in individual(s) with aortic dilatation and incomplete Marfan syndrome (PMID: 16799921, 18781618, 28225382; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg497*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 71 amino acid(s) of the TGFBR2 protein. (less)
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Pathogenic
(Aug 01, 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: SCV000579392.1
First in ClinVar: Jun 18, 2017 Last updated: Jun 18, 2017 |
Comment on evidence:
In a male patient of German origin with Loeys-Dietz syndrome (LDS2; 610168), Singh et al. (2006) identified a c.1489C-T transition in exon 6 of the … (more)
In a male patient of German origin with Loeys-Dietz syndrome (LDS2; 610168), Singh et al. (2006) identified a c.1489C-T transition in exon 6 of the TGFBR2 gene that resulted in premature termination of the protein at arg497 (R497X). Height was 195 cm, while family members were of rather short stature. Dilated ascending aorta without dissection was replaced at a size of 8.0 cm. Involvement of the skeletal system included pectus excavatum, scoliosis, and arachnodactyly with positive thumb and wrist signs. Ocular symptoms were absent. The patient was lost to follow-up. Tooley et al. (2017) reported a 3-generation pedigree with LDS2 segregating the R497X mutation. The proband was a 48-year-old man who had been referred for genetic testing because his maternal cousin had undergone surgery for a dilated aortic root and was found to carry the R497X mutation, prompting cascade testing. The proband had a right inguinal hernia repair at age 14 years, resection of Meckel diverticulum at age 16, and gastric adenocarcinoma at 42 years of age, treated with subtotal gastrectomy and chemotherapy. A dilated aortic root of 43 mm was present at the sinus of Valsalva. His oldest son had hypertelorism, downslanting palpebral fissures, and bifid uvula. Echocardiogram showed a dilated aortic root of 40 mm. The second affected son was diagnosed antenatally with hypoplastic left heart syndrome (HLHS) on ultrasound scan at 20 weeks' gestation. At 12 years of age he had subtle nasal speech but no other features to suggest LDS. At 14 years of age he had developed downslanting palpebral fissures, hypertelorism, and arachnodactyly; these were not appreciated before. The neoascending aorta was found to be 50 mm at that time. The last affected child was 8 months old and had been diagnosed with Loeys-Dietz syndrome, with aortic root measurement at the upper limit of normal. The proband and his 2 older affected sons were being treated with irbesartan. The proband's mother and maternal aunt, ages 73 and 68 years, respectively, were both mutation carriers and were asymptomatic at the time of the proband's diagnosis. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: yes
Allele origin:
unknown
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Centre for Genomic and Experimental Medicine, University of Edinburgh
Accession: SCV000731224.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Clinical Features:
Aneurysm (present) , TAAD Family History (present)
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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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Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. | Weerakkody R | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29543232 |
Extreme phenotypes of Loeys Dietz syndrome. | Tooley MJ | Clinical dysmorphology | 2017 | PMID: 28225382 |
International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). | Jondeau G | Circulation. Cardiovascular genetics | 2016 | PMID: 27879313 |
Loeys Dietz Syndrome and pregnancy: A case report with literature review and a proposed focused management protocol. | Cauldwell M | International journal of cardiology | 2016 | PMID: 27100340 |
Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. | Attias D | Circulation | 2009 | PMID: 19996017 |
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 |
TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. | Singh KK | Human mutation | 2006 | PMID: 16799921 |
Heterozygous TGFBR2 mutations in Marfan syndrome. | Mizuguchi T | Nature genetics | 2004 | PMID: 15235604 |
Text-mined citations for rs863223852 ...
HelpRecord last updated Feb 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.