ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1579G>A (p.Ala527Thr)
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.1579G>A (p.Ala527Thr)
Variation ID: 1066978 Accession: VCV001066978.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30691474 (GRCh38) [ NCBI UCSC ] 3: 30732966 (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 May 10, 2021 Feb 14, 2024 Feb 19, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1579G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Ala527Thr missense NM_001024847.3:c.1654G>A NP_001020018.1:p.Ala552Thr missense NM_001407126.1:c.1762G>A NP_001394055.1:p.Ala588Thr missense NM_001407127.1:c.1687G>A NP_001394056.1:p.Ala563Thr missense NM_001407128.1:c.1606G>A NP_001394057.1:p.Ala536Thr missense NM_001407129.1:c.1582G>A NP_001394058.1:p.Ala528Thr missense NM_001407130.1:c.1576G>A NP_001394059.1:p.Ala526Thr missense NM_001407132.1:c.1474G>A NP_001394061.1:p.Ala492Thr missense NM_001407133.1:c.1474G>A NP_001394062.1:p.Ala492Thr missense NM_001407134.1:c.1474G>A NP_001394063.1:p.Ala492Thr missense NM_001407135.1:c.1474G>A NP_001394064.1:p.Ala492Thr missense NM_001407136.1:c.1474G>A NP_001394065.1:p.Ala492Thr missense NM_001407137.1:c.1294G>A NP_001394066.1:p.Ala432Thr missense NM_001407138.1:c.1219G>A NP_001394067.1:p.Ala407Thr missense NM_001407139.1:c.709G>A NP_001394068.1:p.Ala237Thr missense NC_000003.12:g.30691474G>A NC_000003.11:g.30732966G>A NG_007490.1:g.89973G>A LRG_779:g.89973G>A LRG_779t1:c.1654G>A LRG_779p1:p.Ala552Thr LRG_779t2:c.1579G>A LRG_779p2:p.Ala527Thr - Protein change
- A527T, A552T, A237T, A536T, A407T, A492T, A526T, A432T, A528T, A563T, A588T
- Other names
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- Canonical SPDI
- NC_000003.12:30691473: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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- 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 | ||
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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
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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
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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 | 1094 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 19, 2020 | RCV001378117.5 |
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
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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
(Feb 13, 2020)
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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: SCV002704145.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.A527T variant (also known as c.1579G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide … (more)
The p.A527T variant (also known as c.1579G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1579. The alanine at codon 527 is replaced by threonine, an amino acid with similar properties, and is located in the cbEGF-like #03 domain. This alteration has been detected in individuals with Loeys-Dietz syndrome (LDS), with co-segregation reported in at least two additional affected family members (Poninska JK et al. J Transl Med, 2016 May;14:115; Frischmeyer-Guerrerio PA et al. Sci Transl Med, 2013 Jul;5:195ra94; Guerrerio AL et al. Inflamm. Bowel Dis., 2016 09;22:2058-2062). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 19, 2020)
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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: SCV001575617.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 527 of the TGFBR2 protein … (more)
This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 527 of the TGFBR2 protein (p.Ala527Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 27508510, 27146836). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala527 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16928994, 18852674, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). (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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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 |
Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. | Poninska JK | Journal of translational medicine | 2016 | PMID: 27146836 |
TGFβ receptor mutations impose a strong predisposition for human allergic disease. | Frischmeyer-Guerrerio PA | Science translational medicine | 2013 | PMID: 23884466 |
Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). | Maleszewski JJ | The American journal of surgical pathology | 2009 | PMID: 18852674 |
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 rs2125455285 ...
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.