ClinVar Genomic variation as it relates to human health
NM_003239.5(TGFB3):c.412T>G (p.Ser138Ala)
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(3); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003239.5(TGFB3):c.412T>G (p.Ser138Ala)
Variation ID: 239520 Accession: VCV000239520.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 75971659 (GRCh38) [ NCBI UCSC ] 14: 76438002 (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 6, 2016 May 12, 2024 Mar 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003239.5:c.412T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003230.1:p.Ser138Ala missense NM_001329938.2:c.412T>G NP_001316867.1:p.Ser138Ala missense NM_001329939.2:c.412T>G NP_001316868.1:p.Ser138Ala missense NC_000014.9:g.75971659A>C NC_000014.8:g.76438002A>C NG_011715.1:g.15091T>G LRG_399:g.15091T>G LRG_399t1:c.412T>G - Protein change
- S138A
- Other names
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- Canonical SPDI
- NC_000014.9:75971658:A: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.
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD) 0.00018
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
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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TGFB3 | - | - |
GRCh38 GRCh37 |
585 | 610 |
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
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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 benign (5) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000489572.27 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000660313.10 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 11, 2019 | RCV001193759.8 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 7, 2024 | RCV001171231.11 |
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
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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
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Rienhoff syndrome
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782353.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Uncertain significance
(Jan 17, 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: SCV001333934.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely benign
(Feb 11, 2019)
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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: SCV001362852.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: TGFB3 c.412T>G (p.Ser138Ala) results in a conservative amino acid change located in the TGF-beta, propeptide domain of the encoded protein sequence. Four of … (more)
Variant summary: TGFB3 c.412T>G (p.Ser138Ala) results in a conservative amino acid change located in the TGF-beta, propeptide domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277200 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.412T>G has been reported in the literature in an affected individual (Overwater_2018). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. A co-occurrence with another pathogenic variant has been reported (KCNH2 c.211G>C, p.Gly71Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Oct 03, 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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GeneDx
Accession: SCV000577539.8
First in ClinVar: May 22, 2017 Last updated: Nov 25, 2023 |
Comment:
See Variant Classification Assertion Criteria.
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Uncertain significance
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Rienhoff syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000287909.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 138 of the TGFB3 protein (p.Ser138Ala). … (more)
This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 138 of the TGFB3 protein (p.Ser138Ala). This variant is present in population databases (rs201453600, gnomAD 0.03%). This missense change has been observed in individual(s) with TGFB3-related disease (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 239520). 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 TGFB3 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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Likely benign
(Mar 07, 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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Ambry Genetics
Accession: SCV000739713.5
First in ClinVar: Apr 14, 2018 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, 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: SCV001149270.18
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
TGFB3: BP4
Number of individuals with the variant: 1
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Uncertain significance
(-)
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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: SCV001807486.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Uncertain significance
(-)
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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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928677.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967659.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 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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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management. | Goudal A | Human mutation | 2022 | PMID: 35819174 |
Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. | Overwater E | Human mutation | 2018 | PMID: 29907982 |
Text-mined citations for rs201453600 ...
HelpRecord last updated May 12, 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.