PS4, PS3, PM5
ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1609C>T (p.Arg537Cys)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003242.6(TGFBR2):c.1609C>T (p.Arg537Cys)
Variation ID: 12507 Accession: VCV000012507.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30691504 (GRCh38) [ NCBI UCSC ] 3: 30732996 (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 Aug 22, 2016 May 1, 2024 Dec 26, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003242.6:c.1609C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Arg537Cys missense NM_001024847.3:c.1684C>T NP_001020018.1:p.Arg562Cys missense NM_001407126.1:c.1792C>T NP_001394055.1:p.Arg598Cys missense NM_001407127.1:c.1717C>T NP_001394056.1:p.Arg573Cys missense NM_001407128.1:c.1636C>T NP_001394057.1:p.Arg546Cys missense NM_001407129.1:c.1612C>T NP_001394058.1:p.Arg538Cys missense NM_001407130.1:c.1606C>T NP_001394059.1:p.Arg536Cys missense NM_001407132.1:c.1504C>T NP_001394061.1:p.Arg502Cys missense NM_001407133.1:c.1504C>T NP_001394062.1:p.Arg502Cys missense NM_001407134.1:c.1504C>T NP_001394063.1:p.Arg502Cys missense NM_001407135.1:c.1504C>T NP_001394064.1:p.Arg502Cys missense NM_001407136.1:c.1504C>T NP_001394065.1:p.Arg502Cys missense NM_001407137.1:c.1324C>T NP_001394066.1:p.Arg442Cys missense NM_001407138.1:c.1249C>T NP_001394067.1:p.Arg417Cys missense NM_001407139.1:c.739C>T NP_001394068.1:p.Arg247Cys missense NC_000003.12:g.30691504C>T NC_000003.11:g.30732996C>T NG_007490.1:g.90003C>T LRG_779:g.90003C>T LRG_779t1:c.1684C>T LRG_779p1:p.Arg562Cys LRG_779t2:c.1609C>T LRG_779p2:p.Arg537Cys P37173:p.Arg537Cys - Protein change
- R537C, R562C, R573C, R598C, R502C, R247C, R417C, R442C, R536C, R538C, R546C
- Other names
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p.R537C:CGC>TGC
- Canonical SPDI
- NC_000003.12:30691503: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
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| TGFBR2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1172 | 1199 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 27, 2022 | RCV000013331.24 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2023 | RCV000196289.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 26, 2023 | RCV000529794.11 |
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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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987424.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
|
|
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Pathogenic
(Dec 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Loeys-Dietz syndrome 2
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799079.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS4, PS3, PM5
|
|
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Pathogenic
(Feb 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000250956.14
First in ClinVar: Oct 11, 2015 Last updated: May 06, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in severe impairment of … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in severe impairment of TGF-beta signaling activity (Mizuguchi et al., 2004; Horbelt et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18827873, 26877057, 20628007, 15235604, 21324918, 21098638, 35753512, 30056620, 33083483, 29543232, 35058154, 27112580, 31915033, 18781618) (less)
|
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Likely pathogenic
(Mar 01, 2021)
|
criteria provided, single submitter
Method: research
|
Loeys-Dietz syndrome 2
Affected status: yes
Allele origin:
unknown
|
Centre of Medical Genetics, University of Antwerp
Accession: SCV002025505.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PS1
Sex: male
|
|
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Pathogenic
(Dec 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000658826.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 537 of the TGFBR2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 537 of the TGFBR2 protein (p.Arg537Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related diseases (PMID: 15235604, 18781618, 18827873, 21324918, 25116393, 27112580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12507). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 15235604, 20829218, 21098638). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Pathogenic
(Jul 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002703107.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R537C pathogenic mutation (also known as c.1609C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at … (more)
The p.R537C pathogenic mutation (also known as c.1609C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1609. The arginine at codon 537 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with thoracic aortic aneurysm and dissection (TAAD) (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Aalberts JJ et al. Neth Heart J, 2008 Sep;16:299-304; Stheneur C et al. Hum Mutat, 2008 Nov;29:E284-95; Edelman JJ et al. Interact Cardiovasc Thorac Surg, 2011 May;12:863-5; Luo M et al. Clin Chim Acta, 2016 May;456:144-148; Somers AE et al. Am J Med Genet A, 2016 07;170:1786-90; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Zheng J et al. Int J Legal Med, 2018 Sep;132:1273-1280; Wang Z et al. Biomed Res Int, 2020 Oct;2020:7857043). Additionally, in vitro assays showed this alteration impacts protein function (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Horbelt D et al. J Cell Sci, 2010 Dec;123:4340-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: yes
Allele origin:
unknown
|
Centre for Genomic and Experimental Medicine, University of Edinburgh
Accession: SCV000731239.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Clinical Features:
Aneurysm (present) , TAAD Family History (present)
|
|
|
Pathogenic
(Aug 01, 2004)
|
no assertion criteria provided
Method: literature only
|
LOEYS-DIETZ SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033578.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Mizuguchi et al. (2004) found the mutation 1609C-T in the TGFBR2 gene, resulting in the amino acid substitution arg537-to-cys (R537C), in association with a phenotype … (more)
Mizuguchi et al. (2004) found the mutation 1609C-T in the TGFBR2 gene, resulting in the amino acid substitution arg537-to-cys (R537C), in association with a phenotype identified as Marfan syndrome type 2 (see LDS2, 610168). (less)
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in severe impairment of TGF-beta signaling activity (Mizuguchi et al., 2004; Horbelt et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18827873, 26877057, 20628007, 15235604, 21324918, 21098638, 35753512, 30056620, 33083483, 29543232, 35058154, 27112580, 31915033, 18781618)
Comment:
PM2, PS1
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 537 of the TGFBR2 protein (p.Arg537Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related diseases (PMID: 15235604, 18781618, 18827873, 21324918, 25116393, 27112580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12507). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 15235604, 20829218, 21098638). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R537C pathogenic mutation (also known as c.1609C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1609. The arginine at codon 537 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with thoracic aortic aneurysm and dissection (TAAD) (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Aalberts JJ et al. Neth Heart J, 2008 Sep;16:299-304; Stheneur C et al. Hum Mutat, 2008 Nov;29:E284-95; Edelman JJ et al. Interact Cardiovasc Thorac Surg, 2011 May;12:863-5; Luo M et al. Clin Chim Acta, 2016 May;456:144-148; Somers AE et al. Am J Med Genet A, 2016 07;170:1786-90; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Zheng J et al. Int J Legal Med, 2018 Sep;132:1273-1280; Wang Z et al. Biomed Res Int, 2020 Oct;2020:7857043). Additionally, in vitro assays showed this alteration impacts protein function (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Horbelt D et al. J Cell Sci, 2010 Dec;123:4340-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
PS4, PS3, PM5
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in severe impairment of TGF-beta signaling activity (Mizuguchi et al., 2004; Horbelt et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18827873, 26877057, 20628007, 15235604, 21324918, 21098638, 35753512, 30056620, 33083483, 29543232, 35058154, 27112580, 31915033, 18781618)
Comment:
PM2, PS1
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 537 of the TGFBR2 protein (p.Arg537Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related diseases (PMID: 15235604, 18781618, 18827873, 21324918, 25116393, 27112580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12507). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 15235604, 20829218, 21098638). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R537C pathogenic mutation (also known as c.1609C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1609. The arginine at codon 537 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with thoracic aortic aneurysm and dissection (TAAD) (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Aalberts JJ et al. Neth Heart J, 2008 Sep;16:299-304; Stheneur C et al. Hum Mutat, 2008 Nov;29:E284-95; Edelman JJ et al. Interact Cardiovasc Thorac Surg, 2011 May;12:863-5; Luo M et al. Clin Chim Acta, 2016 May;456:144-148; Somers AE et al. Am J Med Genet A, 2016 07;170:1786-90; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Zheng J et al. Int J Legal Med, 2018 Sep;132:1273-1280; Wang Z et al. Biomed Res Int, 2020 Oct;2020:7857043). Additionally, in vitro assays showed this alteration impacts protein function (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Horbelt D et al. J Cell Sci, 2010 Dec;123:4340-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population. | Wang Z | BioMed research international | 2020 | PMID: 33083483 |
| Genetic diagnosis of acute aortic dissection in South China Han population using next-generation sequencing. | Zheng J | International journal of legal medicine | 2018 | PMID: 30056620 |
| 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 |
| Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome. | Somers AE | American journal of medical genetics. Part A | 2016 | PMID: 27112580 |
| Genetic testing of 10 patients with features of Loeys-Dietz syndrome. | Luo M | Clinica chimica acta; international journal of clinical chemistry | 2016 | PMID: 26877057 |
| Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection. | Wellbrock J | PloS one | 2014 | PMID: 25116393 |
| Familial aortic aneurysm and dissection due to transforming growth factor-beta receptor 2 mutation. | Edelman JJ | Interactive cardiovascular and thoracic surgery | 2011 | PMID: 21324918 |
| Epigenetic control of vascular smooth muscle cells in Marfan and non-Marfan thoracic aortic aneurysms. | Gomez D | Cardiovascular research | 2011 | PMID: 20829218 |
| Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity. | Horbelt D | Journal of cell science | 2010 | PMID: 21098638 |
| The many faces of aggressive aortic pathology: Loeys-Dietz syndrome. | Aalberts JJ | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2008 | PMID: 18827873 |
| 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 |
| Heterozygous TGFBR2 mutations in Marfan syndrome. | Mizuguchi T | Nature genetics | 2004 | PMID: 15235604 |
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Text-mined citations for rs104893809 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.