ClinVar Genomic variation as it relates to human health
NM_004612.4(TGFBR1):c.1285T>C (p.Tyr429His)
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.1285T>C (p.Tyr429His)
Variation ID: 624363 Accession: VCV000624363.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.33 9: 99147683 (GRCh38) [ NCBI UCSC ] 9: 101909965 (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 Mar 31, 2019 Apr 20, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004612.4:c.1285T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004603.1:p.Tyr429His missense NM_001130916.3:c.1054T>C NP_001124388.1:p.Tyr352His missense NM_001306210.2:c.1297T>C NP_001293139.1:p.Tyr433His missense NM_004612.3:c.1285T>C NC_000009.12:g.99147683T>C NC_000009.11:g.101909965T>C NG_007461.1:g.47554T>C - Protein change
- Y429H, Y352H, Y433H
- Other names
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- Canonical SPDI
- NC_000009.12:99147682:T:C
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00007
- Links
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 |
967 | 1044 |
Conditions - Germline
Condition
Help
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV000762568.19 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000802300.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV002470973.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 8, 2023 | RCV003928265.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV003999913.1 |
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
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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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Uncertain significance
(Jan 28, 2021)
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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: SCV001824138.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Reported in one individual diagnosed with medial fibroplasia who had a history of multi-vessel dissection involving the internal carotid and vertebral arteries, ascending aortic aneurysm, … (more)
Reported in one individual diagnosed with medial fibroplasia who had a history of multi-vessel dissection involving the internal carotid and vertebral arteries, ascending aortic aneurysm, marked tortuosity of the descending aorta, no gross craniofacial abnormalities, and a unifid uvula with normal appearing palate (Poloskey et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23064905) (less)
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Uncertain significance
(Apr 27, 2021)
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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: SCV002688975.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.Y429H variant (also known as c.1285T>C), located in coding exon 8 of the TGFBR1 gene, results from a T to C substitution at nucleotide … (more)
The p.Y429H variant (also known as c.1285T>C), located in coding exon 8 of the TGFBR1 gene, results from a T to C substitution at nucleotide position 1285. The tyrosine at codon 429 is replaced by histidine, an amino acid with similar properties. The alteration has been reported in a subject with a history of medial fibroplasia, multi-vessel dissection involving the internal carotid and vertebral arteries, and ectasia of the ascending aorta (Poloskey SL et al. Vasc Med, 2012 Dec;17:371-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766818.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, missense variants have been postulated to exert a dominant negative effect. Both mechanisms are reported in association with Loeys-Dietz syndrome (MIM#609192) (PMID: 30701076). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is considerable variability in the phenotype, from mild features to severe systemic abnormalities and also an overlap in the manifestations with Marfan syndrome, including increased risk of ascending aortic aneurysm and aortic dissection, abnormally long limbs and fingers (PMID: 32339686). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (15 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated protein kinase domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Tyr429Cys) was identified in a prospective Japanese cohort (PMID: 29192238). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in an individual with medial fibroplasia who had a history of multi-vessel dissection involving the internal carotid and vertebral arteries and aneurysm of the ascending aorta; the variant was regarded as VUS (PMID: 23064905). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Feb 16, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001353211.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces tyrosine with histidine at codon 429 of the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces tyrosine with histidine at codon 429 of the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR1-related disorders in the literature. This variant has been identified in 7/282220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 02, 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: SCV000942125.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 429 of the TGFBR1 protein (p.Tyr429His). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 429 of the TGFBR1 protein (p.Tyr429His). This variant is present in population databases (rs201745016, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of nonsyndromic thoracic aortic aneurysms and aortic dissections (TAAD) and/or fibromuscular dysplasia (PMID: 23064905; Invitae). ClinVar contains an entry for this variant (Variation ID: 624363). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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TGFBR1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004740519.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TGFBR1 c.1285T>C variant is predicted to result in the amino acid substitution p.Tyr429His. To our knowledge, this variant has not been reported in the … (more)
The TGFBR1 c.1285T>C variant is predicted to result in the amino acid substitution p.Tyr429His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101909965-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jun 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892900.22
First in ClinVar: Mar 31, 2019 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 4
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Uncertain Significance
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004840429.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces tyrosine with histidine at codon 429 of the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces tyrosine with histidine at codon 429 of the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR1-related disorders in the literature. This variant has been identified in 7/282220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 16
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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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Type A Aortic Dissection Caused by Loeys-Dietz Syndrome with Novel Variation. | Skeik N | Annals of vascular surgery | 2020 | PMID: 32339686 |
Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of TGFBR1. | Hara H | Human genome variation | 2019 | PMID: 30701076 |
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. | Yamaguchi-Kabata Y | Journal of human genetics | 2018 | PMID: 29192238 |
Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia. | Poloskey SL | Vascular medicine (London, England) | 2012 | PMID: 23064905 |
Text-mined citations for rs201745016 ...
HelpRecord last updated Apr 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.