ClinVar Genomic variation as it relates to human health
NM_181486.4(TBX5):c.709C>T (p.Arg237Trp)
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_181486.4(TBX5):c.709C>T (p.Arg237Trp)
Variation ID: 7995 Accession: VCV000007995.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.21 12: 114385522 (GRCh38) [ NCBI UCSC ] 12: 114823327 (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 Jul 17, 2014 May 1, 2024 May 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_181486.4:c.709C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_852259.1:p.Arg237Trp missense NM_000192.3:c.709C>T NP_000183.2:p.Arg237Trp missense NM_080717.4:c.559C>T NP_542448.1:p.Arg187Trp missense NC_000012.12:g.114385522G>A NC_000012.11:g.114823327G>A NG_007373.1:g.27921C>T LRG_670:g.27921C>T LRG_670t1:c.709C>T LRG_670p1:p.Arg237Trp Q99593:p.Arg237Trp - Protein change
- R237W, R187W
- Other names
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- Canonical SPDI
- NC_000012.12:114385521:G:A
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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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TBX5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
678 | 697 |
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
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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Pathogenic (2) |
no assertion criteria provided
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Jun 14, 2018 | RCV000008459.5 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000128627.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2019 | RCV000473181.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2022 | RCV002362570.2 |
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
(Sep 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Aortic valve disease 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552103.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg237 amino acid residue in TBX5. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg237 amino acid residue in TBX5. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10077612, 12499378, 20519243), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This missense change locates in the T-box domain of TBX5 and has been shown in experimental studies to affect TBX5 DNA-binding and TBX5 interaction with NKX2-5, resulting in reduced activation of downstream targets (PMID: 20519243, 12499378, 16380715). This variant has been reported in individuals affected with Holt–Oram syndrome (PMID: 10077762, 12789647) and in a family affected with congenital heart defects (PMID: 25931334). ClinVar contains an entry for this variant (Variation ID: 7995). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 237 of the TBX5 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. (less)
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002662599.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R237W pathogenic mutation (also known as c.709C>T), located in coding exon 6 of the TBX5 gene, results from a C to T substitution at … (more)
The p.R237W pathogenic mutation (also known as c.709C>T), located in coding exon 6 of the TBX5 gene, results from a C to T substitution at nucleotide position 709. The arginine at codon 237 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was initially reported in two probands with Holt-Oram syndrome (Brassington AM et al. Am J Hum Genet, 2003 Jul;73:74-85). This variant has also been detected in individuals and families with atrial and ventricular septal defects (Ambry internal data; Jia Y et al. Am J Med Genet A, 2015 Aug;167A:1822-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration at the same codon, p.R237Q (c.710G>A) has also been described in individuals with Holt-Oram syndrome (Basson CT et al. Nat. Genet., 1997 Jan;15:30-5; Debeer P et al. Clin. Orthop. Relat. Res., 2007 Sep;462:20-6; Vanlerberghe C et al. Eur. J. Hum. Genet., 2019 03;27:360-368). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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not provided
not provided not provided
Affected status: not provided
Allele origin:
germline,
inherited
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Laboratory for Genetics of Human Development Center for Human Genetics, Catholic University of Leuven
Accession: SCV000172245.1
First in ClinVar: Jul 17, 2014 Last updated: Jul 17, 2014
Comment:
this known pathogenic variant causing Holt-Oram Syndrom was identifed in a ASD/VSD family with no obvious upper limb malformations
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Comment:
Converted during submission to Pathogenic.
Observation 1: Observation 2: |
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Pathogenic
(Mar 16, 1999)
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no assertion criteria provided
Method: literature only
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HOLT-ORAM SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028667.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 02, 2016 |
Comment on evidence:
In families with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified an arg237-to-trp substitution in the TBX5 gene. The mutation occurred in the same … (more)
In families with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified an arg237-to-trp substitution in the TBX5 gene. The mutation occurred in the same codon as the arg237-to-gln mutation (601620.0003), and the authors found that both mutations caused extensive upper limb malformations but less significant cardiac abnormalities. They found that residue 80 (601620.0004) is highly conserved within T-box sequences that interact with the major group of target DNA, whereas residue 237 is located in the T-box domain that selectively binds to the minor group DNA. (less)
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Pathogenic
(Jun 14, 2018)
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no assertion criteria provided
Method: clinical testing
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Holt-Oram syndrome
Affected status: yes
Allele origin:
paternal,
unknown
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV000920840.1
First in ClinVar: Jun 14, 2019 Last updated: Jun 14, 2019 |
Observation 1:
Sex: male
Observation 2:
Sex: female
Observation 3:
Sex: male
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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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Identification of deleterious single nucleotide polymorphism (SNP)s in the human TBX5 gene & prediction of their structural & functional consequences: An in silico approach. | Mahfuz AMUB | Biochemistry and biophysics reports | 2021 | PMID: 34917776 |
The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects. | Jia Y | American journal of medical genetics. Part A | 2015 | PMID: 25931334 |
Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations. | Jhang WK | Cardiology in the young | 2015 | PMID: 25216260 |
Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. | Boogerd CJ | Cardiovascular research | 2010 | PMID: 20519243 |
Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. | Koshiba-Takeuchi K | Nature genetics | 2006 | PMID: 16380715 |
Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. | Brassington AM | American journal of human genetics | 2003 | PMID: 12789647 |
Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. | Fan C | The Journal of biological chemistry | 2003 | PMID: 12499378 |
Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. | Basson CT | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 10077612 |
Helicobacter pylori infection and autoimmune processes: an emerging field of study. | Sorrentino D | Italian journal of gastroenterology and hepatology | 1998 | PMID: 10077762 |
Text-mined citations for rs104894382 ...
HelpRecord last updated Jun 23, 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.