ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1336G>A (p.Asp446Asn)
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.1336G>A (p.Asp446Asn)
Variation ID: 265447 Accession: VCV000265447.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30674186 (GRCh38) [ NCBI UCSC ] 3: 30715678 (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 10, 2016 Feb 14, 2024 Sep 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1336G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Asp446Asn missense NM_001024847.3:c.1411G>A NP_001020018.1:p.Asp471Asn missense NM_001407126.1:c.1519G>A NP_001394055.1:p.Asp507Asn missense NM_001407127.1:c.1444G>A NP_001394056.1:p.Asp482Asn missense NM_001407128.1:c.1363G>A NP_001394057.1:p.Asp455Asn missense NM_001407129.1:c.1339G>A NP_001394058.1:p.Asp447Asn missense NM_001407130.1:c.1336G>A NP_001394059.1:p.Asp446Asn missense NM_001407132.1:c.1231G>A NP_001394061.1:p.Asp411Asn missense NM_001407133.1:c.1231G>A NP_001394062.1:p.Asp411Asn missense NM_001407134.1:c.1231G>A NP_001394063.1:p.Asp411Asn missense NM_001407135.1:c.1231G>A NP_001394064.1:p.Asp411Asn missense NM_001407136.1:c.1231G>A NP_001394065.1:p.Asp411Asn missense NM_001407137.1:c.1051G>A NP_001394066.1:p.Asp351Asn missense NM_001407138.1:c.976G>A NP_001394067.1:p.Asp326Asn missense NC_000003.12:g.30674186G>A NC_000003.11:g.30715678G>A NG_007490.1:g.72685G>A LRG_779:g.72685G>A LRG_779t1:c.1411G>A LRG_779p1:p.Asp471Asn LRG_779t2:c.1336G>A LRG_779p2:p.Asp446Asn P37173:p.Asp446Asn - Protein change
- D446N, D471N, D455N, D482N, D507N, D411N, D326N, D351N, D447N
- Other names
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- Canonical SPDI
- NC_000003.12:30674185: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
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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000255277.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2016 | RCV000624602.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 24, 2023 | RCV000692078.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2021 | RCV002245988.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2022 | RCV003401218.4 |
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
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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 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740526.1
First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018 |
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Likely pathogenic
(Mar 01, 2021)
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criteria provided, single submitter
Method: research
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Loeys-Dietz syndrome 2
Affected status: yes
Allele origin:
unknown
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Centre of Medical Genetics, University of Antwerp
Accession: SCV002025504.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PS1, PM1, PP1
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Feb 12, 2017)
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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: SCV002692693.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.D446N pathogenic mutation (also known as c.1336G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at … (more)
The p.D446N pathogenic mutation (also known as c.1336G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1336. The aspartic acid at codon 446 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in multiple unrelated individuals with Loeys-Dietz syndrome (LDS), reported as occurring de novo in a few cases, and described to segregate with disease in a few families (Disabella E et al. Eur. J. Hum. Genet., 2006 Jan;14:34-8; Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Watanabe Y et al. Am. J. Med. Genet. A, 2008 Dec;146A:3070-4; Sousa SB et al. Am. J. Med. Genet. A, 2011 May;155A:1178-83; Ben Amor IM et al. J. Bone Miner. Res., 2012 Mar;27:713-8; Frischmeyer-Guerrerio PA et al. Sci Transl Med, 2013 Jul;5:195ra94; Longmuir SQ et al. J AAPOS, 2014 Jun;18:288-90). Internal structural analysis suggested that this alteration would destabilize the structure of the C-terminal lobe of the kinase domain. 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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Pathogenic
(Jan 09, 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: SCV000322367.8
First in ClinVar: Oct 10, 2016 Last updated: Jan 21, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 23884466, 18781618, 22095581, 16835936, 16251899, 22259224, 32352226, 24792536, 32152251, 19006214, 30219046) (less)
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Likely pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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TGFBR2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120826.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TGFBR2 c.1336G>A variant is predicted to result in the amino acid substitution p.Asp446Asn. This is a recurrent de novo variant that has been reported … (more)
The TGFBR2 c.1336G>A variant is predicted to result in the amino acid substitution p.Asp446Asn. This is a recurrent de novo variant that has been reported in multiple individuals with Loeys-Dietz syndrome (Ben Amor et al. 2012. PubMed ID: 22095581; Jani et al. 2020. PubMed ID: 32152251; Stheneur et al. 2008. PubMed ID: 18781618). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018959.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 24, 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: SCV000819885.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 446 of the TGFBR2 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 446 of the TGFBR2 protein (p.Asp446Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aortic dilation or Loeys-Dietz syndrome (PMID: 16251899, 18781618, 19006214, 21484991, 22095581, 22259224, 23884466, 24792536). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265447). 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. This variant disrupts the p.Asp446 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 21484991), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (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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Primary peripheral retinal nonperfusion in a family with Loeys-Dietz syndrome. | Longmuir SQ | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2014 | PMID: 24792536 |
TGFβ receptor mutations impose a strong predisposition for human allergic disease. | Frischmeyer-Guerrerio PA | Science translational medicine | 2013 | PMID: 23884466 |
Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2, including a type 2 Marfan syndrome familial study. | Zhang L | Molecular vision | 2012 | PMID: 22259224 |
Low bone mass and high material bone density in two patients with Loeys-Dietz syndrome caused by transforming growth factor beta receptor 2 mutations. | Ben Amor IM | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2012 | PMID: 22095581 |
Expanding the skeletal phenotype of Loeys-Dietz syndrome. | Sousa SB | American journal of medical genetics. Part A | 2011 | PMID: 21484991 |
Paternal somatic mosaicism of a TGFBR2 mutation transmitting to an affected son with Loeys-Dietz syndrome. | Watanabe Y | American journal of medical genetics. Part A | 2008 | PMID: 19006214 |
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 |
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 |
Text-mined citations for rs886039551 ...
HelpRecord last updated Mar 17, 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.