ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.859C>T (p.Arg287Trp)
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_005902.4(SMAD3):c.859C>T (p.Arg287Trp)
Variation ID: 30306 Accession: VCV000030306.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67181441 (GRCh38) [ NCBI UCSC ] 15: 67473779 (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 Apr 27, 2014 Feb 14, 2024 Dec 23, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005902.4:c.859C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005893.1:p.Arg287Trp missense NM_001145102.2:c.544C>T NP_001138574.1:p.Arg182Trp missense NM_001145103.2:c.727C>T NP_001138575.1:p.Arg243Trp missense NM_001145104.2:c.274C>T NP_001138576.1:p.Arg92Trp missense NC_000015.10:g.67181441C>T NC_000015.9:g.67473779C>T NG_011990.1:g.120585C>T P84022:p.Arg287Trp - Protein change
- R287W, R182W, R92W, R243W
- Other names
- p.R287W:CGG>TGG
- Canonical SPDI
- NC_000015.10:67181440: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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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SMAD3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
976 | 1034 |
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 (1) |
no assertion criteria provided
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Feb 1, 2011 | RCV000023241.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2021 | RCV000195645.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 23, 2022 | RCV000699559.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2021 | RCV002276569.10 |
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
(Aug 25, 2017)
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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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Blueprint Genetics
Accession: SCV000927381.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(Jun 16, 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: SCV000739683.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R287W pathogenic mutation (also known as c.859C>T), located in coding exon 6 of the SMAD3 gene, results from a C to T substitution at … (more)
The p.R287W pathogenic mutation (also known as c.859C>T), located in coding exon 6 of the SMAD3 gene, results from a C to T substitution at nucleotide position 859. The arginine at codon 287 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with several families with thoracic aortic aneurysms and dissections (TAAD) and osteo-arthritis and has been shown to segregate with disease (van de Laar IM et al. Nat. Genet., 2011 Feb;43:121-6; van de Laar IM et al. J. Med. Genet., 2012 Jan;49:47-57; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Backer J et al. Mol Genet Genomic Med, 2018 May; Ambry internal data). Based on internal structural assessment, this alteration may result in disruption of the interfacial surface of SMAD3 with SMAD2/3/4 (Chacko BM. et al. Mol. Cell. 2004 Sept;15(5):813-23, Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 23, 2022)
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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: SCV000828275.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 287 of the SMAD3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 287 of the SMAD3 protein (p.Arg287Trp). For these reasons, this variant has been classified as Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function. ClinVar contains an entry for this variant (Variation ID: 30306). This missense change has been observed in individuals with aortic aneurysm and osteoarthritis and aneurysms and osteoarthritis syndrome, thoracic aortic aneurysm and dissection, or clinical features of Loeys-Dietz syndrome (PMID: 21217753, 25644172, 29717556; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(May 10, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333408.2
First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021 |
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Pathogenic
(Nov 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002566107.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Pathogenic
(Nov 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: SCV000250761.17
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 30306; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24583347, 29717556, 30661052, 23554019, 22167769, 17994767, 26355014, 22803640, 24135912, 26221609, 21217753, 25644172, 28185953) (less)
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Pathogenic
(Feb 01, 2011)
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no assertion criteria provided
Method: literature only
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LOEYS-DIETZ SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044532.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2014 |
Comment on evidence:
In 20 affected members of a 4-generation Dutch family with arterial aneurysms and dissections and early-onset osteoarthritis (LDS3; 613795), van de Laar et al. (2011) … (more)
In 20 affected members of a 4-generation Dutch family with arterial aneurysms and dissections and early-onset osteoarthritis (LDS3; 613795), van de Laar et al. (2011) identified heterozygosity for an 859C-T transition in exon 6 of the SMAD3 gene, resulting in an arg287-to-trp (R287W) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in 7 unaffected family members or in 544 Dutch control chromosomes. Immunohistochemical analysis of aortic wall tissue from 2 patients showed increased expression of key proteins in the TGF-beta (see TGFB1, 190180) pathway. (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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Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene. | Backer J | Molecular genetics & genomic medicine | 2018 | PMID: 29717556 |
A novel SMAD3 mutation caused multiple aneurysms in a patient without osteoarthritis symptoms. | Courtois A | European journal of medical genetics | 2017 | PMID: 28185953 |
Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. | Campens L | Orphanet journal of rare diseases | 2015 | PMID: 25644172 |
Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. | Wischmeijer A | American journal of medical genetics. Part A | 2013 | PMID: 23554019 |
Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. | van de Laar IM | Journal of medical genetics | 2012 | PMID: 22167769 |
Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. | van de Laar IM | Nature genetics | 2011 | PMID: 21217753 |
Structural basis of heteromeric smad protein assembly in TGF-beta signaling. | Chacko BM | Molecular cell | 2004 | PMID: 15350224 |
Text-mined citations for rs387906850 ...
HelpRecord last updated Mar 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.