ClinVar Genomic variation as it relates to human health
NM_004612.4(TGFBR1):c.680AAG[1] (p.Glu228del)
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_004612.4(TGFBR1):c.680AAG[1] (p.Glu228del)
Variation ID: 213896 Accession: VCV000213896.17
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 9q22.33 9: 99137962-99137964 (GRCh38) [ NCBI UCSC ] 9: 101900244-101900246 (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 29, 2016 May 1, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004612.4:c.680AAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004603.1:p.Glu228del inframe deletion NM_001130916.3:c.449AAG[1] NP_001124388.1:p.Glu151del inframe deletion NM_001306210.2:c.692AAG[1] NP_001293139.1:p.Glu232del inframe deletion NM_004612.2:c.683_685delAAG NC_000009.12:g.99137964AAG[1] NC_000009.11:g.101900246AAG[1] NG_007461.1:g.37835AAG[1] - Protein change
- E228del, E151del, E232del
- Other names
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- Canonical SPDI
- NC_000009.12:99137961:AGAAGAAG:AGAAG
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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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TGFBR1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
975 | 1052 |
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
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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) |
criteria provided, single submitter
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Jul 11, 2022 | RCV000197382.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2022 | RCV000825630.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV001380058.8 |
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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Pathogenic
(Feb 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966987.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Glu228del variant in TGFBR1 has been reported in 4 individuals with clinic al features of Loeys-Dietz Syndrome (LDS), including 3 de novo occurrences (Sthe … (more)
The p.Glu228del variant in TGFBR1 has been reported in 4 individuals with clinic al features of Loeys-Dietz Syndrome (LDS), including 3 de novo occurrences (Sthe neur 2008, Lee 2013, Campens 2015, Li 2017). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 213896) and was absent from larg e population studies, though the ability of these studies to accurately detect i ndels may be limited. This variant is a deletion of 1 amino acid at position 228 and is not predicted to alter the protein reading-frame. It is unclear how this deletion impacts the protein. In summary, this variant meets criteria to be cla ssified as pathogenic for LDS in an autosomal dominant manner based upon its ide ntification in multiple affected individuals, including 3 de novo occurrences, a nd absence in the general population. ACMG/AMP Criteria applied (Richards 2015): PM6_Strong, PM2, PS4_Supporting. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 11, 2022)
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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: SCV000250902.15
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a … (more)
In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 18781618, 27611364, 26877057, 18703712, 25644172, 32152251) (less)
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Pathogenic
(Jul 17, 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: SCV001577993.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant, c.683_685del, results in the deletion of 1 amino acid(s) of the TGFBR1 protein (p.Glu228del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.683_685del, results in the deletion of 1 amino acid(s) of the TGFBR1 protein (p.Glu228del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with TGFBR1-related conditions (PMID: 18781618, 25644172, 29510914; https//doi.org/10.5734/JGM.2013.10.1.47). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213896). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598793.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: TGFBR1 c.683_685delAAG (p.Glu228del) results in an in-frame deletion that is predicted to remove one amino acids from the Protein kinase domain (IPR000719) in … (more)
Variant summary: TGFBR1 c.683_685delAAG (p.Glu228del) results in an in-frame deletion that is predicted to remove one amino acids from the Protein kinase domain (IPR000719) in TGFBR1 protein. The variant was absent in 248038 control chromosomes (gnomAD). c.683_685delAAG has been reported in the literature in multiple individuals affected with Loeys-Dietz Syndrome, including de novo occurrences (Stheneur_2008, Campens_2015, Luo_2016, Hicks_2018, Seo_2018, Yang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 23, 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: SCV002664279.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.683_685delAAG pathogenic mutation (also known as p.E228del), located in coding exon 4 of the TGFBR1 gene, results from an in-frame AAG deletion at nucleotide … (more)
The c.683_685delAAG pathogenic mutation (also known as p.E228del), located in coding exon 4 of the TGFBR1 gene, results from an in-frame AAG deletion at nucleotide positions 683 to 685. This results in the in-frame deletion of a glutamic acid at codon 228, located in the protein kinase domain. This variant has been detected in unrelated individuals reported to have Loeys-Dietz syndrome or related features, including reported de novo occurrences (Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Lee YJ et al. J Genet Med, 2013;10(1):47-51; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Luo M et al. Clin. Chim. Acta, 2016 May;456:144-148). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (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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Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients. | Yang H | Orphanet journal of rare diseases | 2020 | PMID: 31915033 |
The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. | Seo GH | Medicine | 2018 | PMID: 29768367 |
Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center. | Hicks KL | Journal of vascular surgery | 2018 | PMID: 29510914 |
Genetic testing of 248 Chinese aortopathy patients using a panel assay. | Yang H | Scientific reports | 2016 | PMID: 27611364 |
Genetic testing of 10 patients with features of Loeys-Dietz syndrome. | Luo M | Clinica chimica acta; international journal of clinical chemistry | 2016 | PMID: 26877057 |
Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. | Campens L | Orphanet journal of rare diseases | 2015 | PMID: 25644172 |
Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. | Goudie DR | Nature genetics | 2011 | PMID: 21358634 |
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 |
Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. | Valle L | Science (New York, N.Y.) | 2008 | PMID: 18703712 |
https//doi.org/10.5734/JGM.2013.10.1.47 | - | - | - | - |
Text-mined citations for rs863223829 ...
HelpRecord last updated May 01, 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.