ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1382G>A (p.Cys461Tyr)
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.1382G>A (p.Cys461Tyr)
Variation ID: 155839 Accession: VCV000155839.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30674232 (GRCh38) [ NCBI UCSC ] 3: 30715724 (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 Sep 7, 2014 Feb 7, 2023 Sep 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1382G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Cys461Tyr missense NM_001024847.3:c.1457G>A NP_001020018.1:p.Cys486Tyr missense NM_001407126.1:c.1565G>A NP_001394055.1:p.Cys522Tyr missense NM_001407127.1:c.1490G>A NP_001394056.1:p.Cys497Tyr missense NM_001407128.1:c.1409G>A NP_001394057.1:p.Cys470Tyr missense NM_001407129.1:c.1385G>A NP_001394058.1:p.Cys462Tyr missense NM_001407130.1:c.1382G>A NP_001394059.1:p.Cys461Tyr missense NM_001407132.1:c.1277G>A NP_001394061.1:p.Cys426Tyr missense NM_001407133.1:c.1277G>A NP_001394062.1:p.Cys426Tyr missense NM_001407134.1:c.1277G>A NP_001394063.1:p.Cys426Tyr missense NM_001407135.1:c.1277G>A NP_001394064.1:p.Cys426Tyr missense NM_001407136.1:c.1277G>A NP_001394065.1:p.Cys426Tyr missense NM_001407137.1:c.1097G>A NP_001394066.1:p.Cys366Tyr missense NM_001407138.1:c.1022G>A NP_001394067.1:p.Cys341Tyr missense NC_000003.12:g.30674232G>A NC_000003.11:g.30715724G>A NG_007490.1:g.72731G>A LRG_779:g.72731G>A LRG_779t1:c.1457G>A LRG_779p1:p.Cys486Tyr LRG_779t2:c.1382G>A LRG_779p2:p.Cys461Tyr - Protein change
- C461Y, C486Y, C470Y, C497Y, C341Y, C426Y, C522Y, C462Y, C366Y
- Other names
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- Canonical SPDI
- NC_000003.12:30674231:G: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
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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
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
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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) |
no assertion criteria provided
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Nov 26, 2013 | RCV000143955.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2022 | RCV002283457.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2021 | RCV002515939.1 |
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
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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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Likely pathogenic
(Sep 01, 2022)
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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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3billion
Accession: SCV002573242.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000155839 / PMID: 16928994). A different missense change at the same codon (p.Cys461Arg) has been reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000393299 / PMID: 28344185). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Scoliosis (present) , Joint hypermobility (present) , Arachnodactyly (present) , Hyperextensible skin (present) , Cutis laxa (present) , Pectus excavatum (present) , Exodeviation (present) , … (more)
Scoliosis (present) , Joint hypermobility (present) , Arachnodactyly (present) , Hyperextensible skin (present) , Cutis laxa (present) , Pectus excavatum (present) , Exodeviation (present) , Generalized hypotonia (present) , Frontal bossing (present) (less)
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Likely pathogenic
(Apr 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003558433.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.1382G>A (p.C461Y) alteration is located in exon 5 (coding exon 5) of the TGFBR2 gene. This alteration results from a G to A substitution … (more)
The c.1382G>A (p.C461Y) alteration is located in exon 5 (coding exon 5) of the TGFBR2 gene. This alteration results from a G to A substitution at nucleotide position 1382, causing the cysteine (C) at amino acid position 461 to be replaced by a tyrosine (Y). Based on data from the Genome Aggregation Database (gnomAD), the TGFBR2 c.1382G>A alteration was not observed, with coverage at this position. This alteration has been previously reported in individuals with Loeys-Dietz syndrome type I (Loeys, 2006). Using alternate nomenclature, this variant (p.C486Y, c.1457G>A) has also been reported de novo in a patient with an atrial septal defect (Jin, 2017). Another alteration affecting the same amino acid, p.C461R, was reported in a neonatal female patient with features consistent with Loeys-Dietz syndrome (Valenzuela, 2017). The p.C461 amino acid is conserved in available vertebrate species. The p.C461Y alteration is located in the kinase domain of TGFBR2. Based on internal structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Tebben, 2016; Zimmermann, 2017). Functional analysis in fibroblasts explanted from a patient with the p.C461Y alteration showed disruption of fibroblast transformation into myofibroblasts with TGF-B1 stimulation; however, the clinical relevance of those results is unclear (Inamoto, 2010). The in silico prediction for the p.C461Y alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 26, 2013)
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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: SCV000188835.1
First in ClinVar: Sep 07, 2014 Last updated: Sep 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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Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. | Jin SC | Nature genetics | 2017 | PMID: 28991257 |
Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation. | Valenzuela I | European journal of medical genetics | 2017 | PMID: 28344185 |
Molecular modeling and molecular dynamic simulation of the effects of variants in the TGFBR2 kinase domain as a paradigm for interpretation of variants obtained by next generation sequencing. | Zimmermann MT | PloS one | 2017 | PMID: 28182693 |
Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity. | Tebben AJ | Acta crystallographica. Section D, Structural biology | 2016 | PMID: 27139629 |
TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. | Inamoto S | Cardiovascular research | 2010 | PMID: 20628007 |
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 rs587782979 ...
HelpRecord last updated Feb 25, 2023
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.