ClinVar Genomic variation as it relates to human health
NM_003238.6(TGFB2):c.958C>T (p.Arg320Cys)
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_003238.6(TGFB2):c.958C>T (p.Arg320Cys)
Variation ID: 495213 Accession: VCV000495213.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 218437368 (GRCh38) [ NCBI UCSC ] 1: 218610710 (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 11, 2018 Aug 11, 2024 Apr 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003238.6:c.958C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003229.1:p.Arg320Cys missense NM_001135599.4:c.1042C>T NP_001129071.1:p.Arg348Cys missense NR_138148.2:n.2209C>T non-coding transcript variant NR_138149.2:n.2293C>T non-coding transcript variant NC_000001.11:g.218437368C>T NC_000001.10:g.218610710C>T NG_027721.2:g.97035C>T - Protein change
- R348C, R320C
- Other names
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- Canonical SPDI
- NC_000001.11:218437367:C:T
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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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TGFB2 | - | - |
GRCh38 GRCh37 |
635 | 718 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 3, 2023 | RCV000585795.24 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2022 | RCV002225683.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2024 | RCV004678752.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 4
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160578.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The TGFB2 c.958C>T; p.Arg320Cys variant (rs1553303352), also known as p.Arg348Cys using alternative nomenclature, is reported in the literature in multiple individuals affected with aortic aneurysm … (more)
The TGFB2 c.958C>T; p.Arg320Cys variant (rs1553303352), also known as p.Arg348Cys using alternative nomenclature, is reported in the literature in multiple individuals affected with aortic aneurysm or dissection (Al Maskari 2016, Gago-Diaz 2014). This variant was observed to cosegregate with disease in multiple affected individuals in at least two families, although its detection in some unaffected relatives suggests it may exhibit incomplete penetrance (Al Maskari 2016, Gago-Diaz 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported in ClinVar (Variation ID: 495213). The arginine at codon 320 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, immunoblotting and immunofluorescence of aortic tissue from an affected individual with this variant exhibited substantially increased levels of TGFB1 and TGFB2 protein compared to unaffected controls (Al Maskari 2016). An increase in TGFB2 in affected aortic tissue may be an indirect effect of haploinsufficiency in aortic disease (Boileau 2012). Based on available information, this variant is considered to be likely pathogenic. References: Al Maskari R et al. A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. Eur J Hum Genet. 2016 Jan;25(1):157-160. Boileau C et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012 Jul 8;44(8):916-21. Gago-Diaz M et al. Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease. Clin Chim Acta. 2014 Nov 1;437:88-92. (less)
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Likely pathogenic
(Dec 23, 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: SCV002504220.2
First in ClinVar: Apr 30, 2022 Last updated: Dec 31, 2022 |
Comment:
Reported in two unrelated individuals with non-syndromic aortic disease and Loeys-Dietz syndrome type 4 (LDS4) (also reported as p.(R348C) due to alternate nomenclature), and segregates … (more)
Reported in two unrelated individuals with non-syndromic aortic disease and Loeys-Dietz syndrome type 4 (LDS4) (also reported as p.(R348C) due to alternate nomenclature), and segregates with disease in affected family members from these two families (Gago-Diaz et al., 2014; Al Maskari et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25046559, 27782106) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 4
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013720.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495213 / PMID: 25046559). A different missense change at the same codon (p.Arg320His) has been reported to be associated with TGFB2 related disorder (PMID: 33418956). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Complete atrioventricular canal (present)
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 4
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001420990.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 320 of the TGFB2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 320 of the TGFB2 protein (p.Arg320Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TGFB2-related conditions (PMID: 25046559, 27782106; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495213). 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 expected to disrupt TGFB2 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 25, 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: SCV005170142.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.R320C variant (also known as c.958C>T), located in coding exon 6 of the TGFB2 gene, results from a C to T substitution at nucleotide … (more)
The p.R320C variant (also known as c.958C>T), located in coding exon 6 of the TGFB2 gene, results from a C to T substitution at nucleotide position 958. The arginine at codon 320 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant (also referred to as NM_001135599.2:c.1042C>T, p.R348C) was reported in unrelated individuals with thoracic aortic aneurysm and dissection with and without mild systemic connective tissue disease features, and segregated with disease in families (Gago-Díaz M et al. Clin. Chim. Acta, 2014 Nov;437:88-92; Al Maskari R et al. Eur. J. Hum. Genet., 2016 01;25:157-160). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Mar 06, 2018)
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no assertion criteria provided
Method: literature only
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LOEYS-DIETZ SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000693725.1
First in ClinVar: Mar 11, 2018 Last updated: Mar 11, 2018 |
Comment on evidence:
In 3 affected members of a 4-generation Spanish family with autosomal dominant thoracic aortic aneurysm (LDS4; 614816), Gago-Diaz et al. (2014) identified a C-to-T transition … (more)
In 3 affected members of a 4-generation Spanish family with autosomal dominant thoracic aortic aneurysm (LDS4; 614816), Gago-Diaz et al. (2014) identified a C-to-T transition at nucleotide 1042 of the TGFB2 gene (c.1042C-T, NM_001135599.2), which resulted in an arginine-to-cystine substitution at codon 348 (R348C). Affected members had minor connective tissue disease signs such as joint laxity, scoliosis, flat feet, dolichocephaly, and high palate. One affected member had a bicuspid aortic valve. Two unaffected individuals, ages 14 and 44 years, were found to carry the mutation, suggesting possible later development or incomplete penetrance, respectively. The variant was not detected in the Exome Variant Server, HGMD, or in the Locus Specific Database list, and was not present in the ExAC database (March 2018). (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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Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes. | Haug P | Genes | 2021 | PMID: 33418956 |
A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. | Al Maskari R | European journal of human genetics : EJHG | 2016 | PMID: 27782106 |
Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease. | Gago-Díaz M | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 25046559 |
Text-mined citations for rs1553303352 ...
HelpRecord last updated Sep 29, 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.