ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys)
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
-
NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys)
Variation ID: 12514 Accession: VCV000012514.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p24.1 3: 30674228 (GRCh38) [ NCBI UCSC ] 3: 30715720 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 27, 2014 Apr 20, 2024 Dec 4, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003242.6:c.1378C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Arg460Cys missense NM_001024847.3:c.1453C>T NP_001020018.1:p.Arg485Cys missense NM_001407126.1:c.1561C>T NP_001394055.1:p.Arg521Cys missense NM_001407127.1:c.1486C>T NP_001394056.1:p.Arg496Cys missense NM_001407128.1:c.1405C>T NP_001394057.1:p.Arg469Cys missense NM_001407129.1:c.1381C>T NP_001394058.1:p.Arg461Cys missense NM_001407130.1:c.1378C>T NP_001394059.1:p.Arg460Cys missense NM_001407132.1:c.1273C>T NP_001394061.1:p.Arg425Cys missense NM_001407133.1:c.1273C>T NP_001394062.1:p.Arg425Cys missense NM_001407134.1:c.1273C>T NP_001394063.1:p.Arg425Cys missense NM_001407135.1:c.1273C>T NP_001394064.1:p.Arg425Cys missense NM_001407136.1:c.1273C>T NP_001394065.1:p.Arg425Cys missense NM_001407137.1:c.1093C>T NP_001394066.1:p.Arg365Cys missense NM_001407138.1:c.1018C>T NP_001394067.1:p.Arg340Cys missense NC_000003.12:g.30674228C>T NC_000003.11:g.30715720C>T NG_007490.1:g.72727C>T LRG_779:g.72727C>T LRG_779t1:c.1453C>T LRG_779p1:p.Arg485Cys LRG_779t2:c.1378C>T LRG_779p2:p.Arg460Cys P37173:p.Arg460Cys - Protein change
- R460C, R485C, R340C, R425C, R469C, R365C, R461C, R496C, R521C
- Other names
- p.R460C:CGC>TGC
- Canonical SPDI
- NC_000003.12:30674227:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | 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. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, single submitter
|
Nov 28, 2023 | RCV000013339.25 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 4, 2013 | RCV000252297.2 | |
Pathogenic (3) |
criteria provided, single submitter
|
Feb 10, 2022 | RCV000199227.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 4, 2023 | RCV000654788.7 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Feb 04, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000318324.5
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000250946.15
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple individuals with familial thoracic aortic aneurysm and dissection (TAAD) and in individuals who met diagnostic criteria for Marfan syndrome (Pannu et al., … (more)
Reported in multiple individuals with familial thoracic aortic aneurysm and dissection (TAAD) and in individuals who met diagnostic criteria for Marfan syndrome (Pannu et al., 2005; Singh et al., 2006; Tran-Fadulu et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and in vitro assays have demonstrated that R460C affects protein trafficking, exhibits a dominant-negative effect, and fails to induce extracellular signal-regulated kinase (ERK) signaling activity (Horbelt et al., 2010).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21267002, 25644172, 19159394, 16251899, 27508510, 16799921, 23685554, 23276923, 28152038, 16027248, 19542084, 21098638) (less)
|
|
Pathogenic
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Loeys-Dietz syndrome 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004839378.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD), and it has been reported to co-segregate with TAAD in … (more)
This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD), and it has been reported to co-segregate with TAAD in multiple families (PMID: 16799921, 16027248, 19159394, 19542084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 21098638). A different missense substitution at this amino acid residue, p.Arg460His, has been previously reported in individuals with TAAD and Loeys-Dietz syndrome, and it is classified as pathogenic (ClinVar variation ID 12515), which supports the functional importance of this position. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000776687.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 460 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 460 of the TGFBR2 protein (p.Arg460Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related disease (PMID: 16027248, 16799921, 19159394, 19542084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12514). 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: 21098638). This variant disrupts the p.Arg460 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16027248, 16251899, 21267002, 25644172, 27508510; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 26, 2005)
|
no assertion criteria provided
Method: literature only
|
LOEYS-DIETZ SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033586.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2014 |
Comment on evidence:
In 2 families with thoracic aortic aneurysm and dissection mapping to chromosome 3p25-p24 (LDS2; 610168), Pannu et al. (2005) detected a 1378C-T transition in exon … (more)
In 2 families with thoracic aortic aneurysm and dissection mapping to chromosome 3p25-p24 (LDS2; 610168), Pannu et al. (2005) detected a 1378C-T transition in exon 5 of the TGFBR2 gene that resulted in the substitution of cysteine for arginine at amino acid 460 (R460C). The clinical features of one of these families had been reported by Hasham et al. (2003). The proband of the second family, a 4-generation family with autosomal dominant thoracic aortic aneurysm and dissection, presented at 41 years of age with an aneurysm of the ascending aorta and mitral valve prolapse. Affected members of the family presented primarily with type A dissections. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808087.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967803.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
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 |
---|---|---|---|---|
Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFβ. | Guerrerio AL | Inflammatory bowel diseases | 2016 | PMID: 27508510 |
Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. | Campens L | Orphanet journal of rare diseases | 2015 | PMID: 25644172 |
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 |
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 |
Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. | Tran-Fadulu V | Journal of medical genetics | 2009 | PMID: 19542084 |
Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. | Söylen B | Clinical genetics | 2009 | PMID: 19159394 |
TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. | Singh KK | Human mutation | 2006 | PMID: 16799921 |
Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. | Disabella E | European journal of human genetics : EJHG | 2006 | PMID: 16251899 |
Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. | Pannu H | Circulation | 2005 | PMID: 16027248 |
Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24-25. | Hasham SN | Circulation | 2003 | PMID: 12821554 |
Text-mined citations for rs104893811 ...
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.