ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.985G>A (p.Ala329Thr)
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.
Uncertain significance(2); Benign(1); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003242.6(TGFBR2):c.985G>A (p.Ala329Thr)
Variation ID: 161395 Accession: VCV000161395.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30672168 (GRCh38) [ NCBI UCSC ] 3: 30713660 (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 Dec 7, 2014 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.985G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Ala329Thr missense NM_001024847.3:c.1060G>A NP_001020018.1:p.Ala354Thr missense NM_001407126.1:c.1168G>A NP_001394055.1:p.Ala390Thr missense NM_001407127.1:c.1093G>A NP_001394056.1:p.Ala365Thr missense NM_001407128.1:c.1012G>A NP_001394057.1:p.Ala338Thr missense NM_001407129.1:c.988G>A NP_001394058.1:p.Ala330Thr missense NM_001407130.1:c.985G>A NP_001394059.1:p.Ala329Thr missense NM_001407132.1:c.880G>A NP_001394061.1:p.Ala294Thr missense NM_001407133.1:c.880G>A NP_001394062.1:p.Ala294Thr missense NM_001407134.1:c.880G>A NP_001394063.1:p.Ala294Thr missense NM_001407135.1:c.880G>A NP_001394064.1:p.Ala294Thr missense NM_001407136.1:c.880G>A NP_001394065.1:p.Ala294Thr missense NM_001407137.1:c.700G>A NP_001394066.1:p.Ala234Thr missense NM_001407138.1:c.625G>A NP_001394067.1:p.Ala209Thr missense NC_000003.12:g.30672168G>A NC_000003.11:g.30713660G>A NG_007490.1:g.70667G>A LRG_779:g.70667G>A LRG_779t1:c.1060G>A LRG_779p1:p.Ala354Thr LRG_779t2:c.985G>A LRG_779p2:p.Ala329Thr - Protein change
- A354T, A329T, A330T, A338T, A390T, A209T, A234T, A294T, A365T
- Other names
- p.A329T:GCC>ACC
- Canonical SPDI
- NC_000003.12:30672167: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.
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00010
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
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. |
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TGFBR2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1148 | 1174 |
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jun 1, 2014 | RCV000148892.11 | |
Benign (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV000987136.10 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000864105.19 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV001704074.17 | |
Likely benign (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV003905278.1 |
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
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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Uncertain significance
(Jun 01, 2014)
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criteria provided, single submitter
Method: research
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Loeys-Dietz aortic aneurysm syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190638.2 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
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Likely benign
(Nov 06, 2020)
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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: SCV000250928.10
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
This variant is associated with the following publications: (PMID: 21267002, 16928994, 24055113, 25637381, 23884466, 17061023, 30739908, 32152251)
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Uncertain significance
(May 10, 2021)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002050041.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The TGFBR2 c.985G>A; p.Ala329Thr variant (rs149425237) has been identified in multiple individuals included in cohorts of Loeys-Dietz syndrome patients or thoracic aortic aneurysms and dissections … (more)
The TGFBR2 c.985G>A; p.Ala329Thr variant (rs149425237) has been identified in multiple individuals included in cohorts of Loeys-Dietz syndrome patients or thoracic aortic aneurysms and dissections (TAAD; Barnett 2011, Frischmeyer-Guerrerio 2013, Jani 2020, Loeys 2006). However, this variant is found in the general population with an allele frequency in Ashkenazi Jewish individuals of 0.19% (20/10,346 alleles) in the Genome Aggregation Database. The alanine at codon 329 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.59). Based on the available information, the clinical significance of this variant is uncertain. References: Barnett et al. Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? Eur J Hum Genet. 2011 Jun;19(6):624-33. PMID: 21267002 Frischmeyer-Guerrerio et al. TGFß receptor mutations impose a strong predisposition for human allergic disease. Sci Transl Med. 2013 Jul 24;5(195):195ra94. PMID: 23884466 Jani et al. Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation. J Med Genet. 2020 Oct;57(10):699-707. PMID: 32152251 Loeys et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. PMID: 16928994 (less)
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001136354.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Likely benign
(Nov 08, 2018)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001354420.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Likely benign
(Jan 22, 2024)
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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: SCV001004863.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Likely benign
(Aug 22, 2023)
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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: SCV004720102.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Apr 11, 2022)
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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: SCV002693217.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Apr 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005042282.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
TGFBR2: BS2
Number of individuals with the variant: 1
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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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Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation. | Jani P | Journal of medical genetics | 2020 | PMID: 32152251 |
Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). | Arnaud P | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30739908 |
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 rs148665451 ...
HelpRecord last updated May 19, 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.