ClinVar Genomic variation as it relates to human health
NM_004612.4(TGFBR1):c.52GCG[10] (p.Ala26dup)
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(1); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004612.4(TGFBR1):c.52GCG[10] (p.Ala26dup)
Variation ID: 213864 Accession: VCV000213864.44
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 9q22.33 9: 99105255-99105256 (GRCh38) [ NCBI UCSC ] 9: 101867537-101867538 (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 19, 2017 Oct 8, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004612.4:c.52GCG[10] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004603.1:p.Ala26dup inframe insertion NM_004612.4:c.76_78dupGCG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001130916.3:c.52GCG[10] NP_001124388.1:p.Ala26dup inframe insertion NM_001306210.2:c.52GCG[10] NP_001293139.1:p.Ala26dup inframe insertion NM_004612.2:c.76_78dup NM_004612.3:c.76_78dupGCG NC_000009.12:g.99105257GCG[10] NC_000009.11:g.101867539GCG[10] NG_007461.1:g.5128GCG[10] - Protein change
- Other names
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- Canonical SPDI
- NC_000009.12:99105255:GGCGGCGGCGGCGGCGGCGGCGGCGGCG:GGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG
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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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0.05132 (GGCGGCGGCGGCGGCGGCG)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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
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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TGFBR1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
988 | 1065 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 25, 2022 | RCV000195794.16 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000526310.19 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV001579589.20 | |
TGFBR1-related disorder
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Likely benign (1) |
no assertion criteria provided
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Mar 11, 2020 | RCV003937726.2 |
Likely benign (1) |
criteria provided, single submitter
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May 4, 2023 | RCV003993883.1 |
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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Likely benign
(May 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple self-healing squamous epithelioma
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812832.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
South Asian population allele frequency is 0.1502% (rs11466445, 12/4610 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, … (more)
South Asian population allele frequency is 0.1502% (rs11466445, 12/4610 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 (less)
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Likely benign
(Jan 08, 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: SCV000250867.8
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 29768367, 30487145, 11746979, 10582683, 16204663)
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Likely benign
(Jan 15, 2019)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333555.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely benign
(Jul 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363334.3
First in ClinVar: Jun 22, 2020 Last updated: Sep 17, 2022 |
Comment:
Variant summary: TGFBR1 c.76_78dupGCG (p.Ala26dup) causes the insertion of 3 nucleotides into exon 1 of the TGFBR1 mRNA that results in an in-frame insertion of … (more)
Variant summary: TGFBR1 c.76_78dupGCG (p.Ala26dup) causes the insertion of 3 nucleotides into exon 1 of the TGFBR1 mRNA that results in an in-frame insertion of an Alanine residue into a polyalanine stretch (consisting of 9 Alanines) in the encoded protein sequence. The variant is also described as TGFBR1*10A in the literature. The variant allele was found at a frequency of 0.00067 in 26720 control chromosomes (gnomAD). The observed variant frequency is approximately 360-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06), strongly suggesting that the variant is benign. Though these data must be evaluated with caution, as this region is indicated to be of poor quality in the gnomAD database. The variant, c.76_78dupGCG, has been reported in the literature in an individual with suspected Loeys-Dietz Syndrome (example, Seo_2018), but was also found in healthy controls (Samowitz_2001, Rego_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect for this variant on either targeting to or translocation across the endoplasmic reticulum membrane as well as no impact on TGF-beta signaling (example, Pasche_1999, Pasche_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as lilely benign (n=5) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Apr 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067555.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Nov 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000702913.2
First in ClinVar: Apr 02, 2018 Last updated: Aug 12, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Feb 01, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000658857.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Sep 08, 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: SCV002673739.2
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
(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: SCV002545702.15
First in ClinVar: Jul 09, 2022 Last updated: Oct 08, 2024 |
Comment:
TGFBR1: BS1
Number of individuals with the variant: 8
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Likely benign
(Mar 11, 2020)
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no assertion criteria provided
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: SCV004747475.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 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
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807819.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956560.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. | Seo GH | Medicine | 2018 | PMID: 29768367 |
TGFBR1 signaling and breast cancer. | Moore-Smith L | Journal of mammary gland biology and neoplasia | 2011 | PMID: 21461994 |
TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk. | Skoglund Lundin J | British journal of cancer | 2009 | PMID: 19401691 |
TGF-beta signaling alterations and susceptibility to colorectal cancer. | Xu Y | Human molecular genetics | 2007 | PMID: 17613544 |
Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. | Skoglund J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17575241 |
Somatic acquisition and signaling of TGFBR1*6A in cancer. | Pasche B | JAMA | 2005 | PMID: 16204663 |
TGFBR1*6A is not associated with prostate cancer in men of European ancestry. | Suarez BK | Prostate cancer and prostatic diseases | 2005 | PMID: 15505640 |
Uncommon TGFBRI allele is not associated with increased susceptibility to colon cancer. | Samowitz WS | Genes, chromosomes & cancer | 2001 | PMID: 11746979 |
TbetaR-I(6A) is a candidate tumor susceptibility allele. | Pasche B | Cancer research | 1999 | PMID: 10582683 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TGFBR1 | - | - | - | - |
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Text-mined citations for rs11466445 ...
HelpRecord last updated Oct 13, 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.