ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1583G>A (p.Arg528His)
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.1583G>A (p.Arg528His)
Variation ID: 12511 Accession: VCV000012511.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30691478 (GRCh38) [ NCBI UCSC ] 3: 30732970 (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 Jun 1, 2016 Feb 14, 2024 Aug 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1583G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Arg528His missense NM_001024847.3:c.1658G>A NP_001020018.1:p.Arg553His missense NM_001407126.1:c.1766G>A NP_001394055.1:p.Arg589His missense NM_001407127.1:c.1691G>A NP_001394056.1:p.Arg564His missense NM_001407128.1:c.1610G>A NP_001394057.1:p.Arg537His missense NM_001407129.1:c.1586G>A NP_001394058.1:p.Arg529His missense NM_001407130.1:c.1580G>A NP_001394059.1:p.Arg527His missense NM_001407132.1:c.1478G>A NP_001394061.1:p.Arg493His missense NM_001407133.1:c.1478G>A NP_001394062.1:p.Arg493His missense NM_001407134.1:c.1478G>A NP_001394063.1:p.Arg493His missense NM_001407135.1:c.1478G>A NP_001394064.1:p.Arg493His missense NM_001407136.1:c.1478G>A NP_001394065.1:p.Arg493His missense NM_001407137.1:c.1298G>A NP_001394066.1:p.Arg433His missense NM_001407138.1:c.1223G>A NP_001394067.1:p.Arg408His missense NM_001407139.1:c.713G>A NP_001394068.1:p.Arg238His missense NC_000003.12:g.30691478G>A NC_000003.11:g.30732970G>A NG_007490.1:g.89977G>A LRG_779:g.89977G>A LRG_779t1:c.1658G>A LRG_779p1:p.Arg553His LRG_779t2:c.1583G>A LRG_779p2:p.Arg528His P37173:p.Arg528His - Protein change
- R528H, R553H, R238H, R408H, R537H, R564H, R589H, R433H, R529H, R493H, R527H
- Other names
- p.R528H:CGT>CAT
- Canonical SPDI
- NC_000003.12:30691477: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
Help
The frequency of the allele represented by this VCV record.
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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 | ||
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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 |
1068 | 1093 |
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
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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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Mar 1, 2005 | RCV000013336.7 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2005 | RCV000013335.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 29, 2014 | RCV000211858.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 21, 2019 | RCV000200178.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 7, 2023 | RCV000654809.5 |
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
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
(May 21, 2019)
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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: SCV000250955.14
First in ClinVar: Oct 11, 2015 Last updated: Mar 08, 2017 |
Comment:
Reported in ClinVar as pathogenic but additional evidence is not available (ClinVar Variant ID# 12511; Landrum et al., 2016); Not observed in large population cohorts … (more)
Reported in ClinVar as pathogenic but additional evidence is not available (ClinVar Variant ID# 12511; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate variant has a dominant-negative effect on the TGFBR2 gene (Horbelt et al., 2010; Inamoto et al., 2010; Barnett et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22488992, 30406707, 15731757, 21267002, 21098638, 17470566, 18781618, 19996017, 20628007, 23103230, 16791849, 23884466, 27879313, 16928994, 27508510, 31536524, 32152251) (less)
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Pathogenic
(Aug 07, 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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Invitae
Accession: SCV000776709.4
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. ClinVar contains an entry for this variant (Variation ID: 12511). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 15731757, 16928994, 19996017, 20956634, 22488992, 23103230, 25116393). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the TGFBR2 protein (p.Arg528His). (less)
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Pathogenic
(Aug 29, 2014)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203966.5
First in ClinVar: Jan 31, 2015 Last updated: Jun 01, 2016 |
Comment:
The Arg528His variant in TGFBR2 has been identified in >8 individuals with Loeys -Dietz syndrome and was found to occur de novo in one of … (more)
The Arg528His variant in TGFBR2 has been identified in >8 individuals with Loeys -Dietz syndrome and was found to occur de novo in one of these individuals (Loey s 2005, Loeys 2006, LMM unpublished data). It was absent from large population s tudies. In vitro and in vivo functional studies provide evidence that the Arg528 His variant may impact protein function. Computational prediction tools and cons ervation analysis suggest that the Arg528His variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM). (less)
Number of individuals with the variant: 2
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Pathogenic
(Mar 01, 2005)
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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:
unknown
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OMIM
Accession: SCV000033582.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In their family 2, Loeys et al. (2005) demonstrated that the single case of Loeys-Dietz syndrome (LDS2; 610168) was heterozygous for a 1583G-A transition in … (more)
In their family 2, Loeys et al. (2005) demonstrated that the single case of Loeys-Dietz syndrome (LDS2; 610168) was heterozygous for a 1583G-A transition in exon 7 of the TGFBR2 gene that resulted in an arg528-to-his (R528H) amino acid substitution. R528H had been reported as a somatic event in colon cancer and shown to cause loss of function in a transient transfection assay (Grady et al., 1999). (less)
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Pathogenic
(Mar 01, 2005)
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no assertion criteria provided
Method: literature only
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COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 6, SOMATIC
Affected status: not provided
Allele origin:
somatic
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OMIM
Accession: SCV000033583.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In their family 2, Loeys et al. (2005) demonstrated that the single case of Loeys-Dietz syndrome (LDS2; 610168) was heterozygous for a 1583G-A transition in … (more)
In their family 2, Loeys et al. (2005) demonstrated that the single case of Loeys-Dietz syndrome (LDS2; 610168) was heterozygous for a 1583G-A transition in exon 7 of the TGFBR2 gene that resulted in an arg528-to-his (R528H) amino acid substitution. R528H had been reported as a somatic event in colon cancer and shown to cause loss of function in a transient transfection assay (Grady et al., 1999). (less)
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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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Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection. | Wellbrock J | PloS one | 2014 | PMID: 25116393 |
In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. | Carmignac V | American journal of human genetics | 2012 | PMID: 23103230 |
Loeys-Dietz syndrome presenting as respiratory distress due to pulmonary artery dilation. | Kuppler KM | American journal of medical genetics. Part A | 2012 | PMID: 22488992 |
Multiple facial milia in patients with Loeys-Dietz syndrome. | Lloyd BM | Archives of dermatology | 2011 | PMID: 20956634 |
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 |
Aneurysm syndromes caused by mutations in the TGF-beta receptor. | Loeys BL | The New England journal of medicine | 2006 | PMID: 16928994 |
A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. | Loeys BL | Nature genetics | 2005 | PMID: 15731757 |
Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. | Grady WM | Cancer research | 1999 | PMID: 9927040 |
Text-mined citations for rs104893815 ...
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.