ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.802C>T (p.Arg268Cys)
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.802C>T (p.Arg268Cys)
Variation ID: 198187 Accession: VCV000198187.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67181384 (GRCh38) [ NCBI UCSC ] 15: 67473722 (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 29, 2016 Feb 20, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005902.4:c.802C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005893.1:p.Arg268Cys missense NM_001145102.2:c.487C>T NP_001138574.1:p.Arg163Cys missense NM_001145103.2:c.670C>T NP_001138575.1:p.Arg224Cys missense NM_001145104.2:c.217C>T NP_001138576.1:p.Arg73Cys missense NC_000015.10:g.67181384C>T NC_000015.9:g.67473722C>T NG_011990.1:g.120528C>T - Protein change
- R268C, R73C, R224C, R163C
- Other names
- p.R268C:CGC>TGC
- Canonical SPDI
- NC_000015.10:67181383: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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SMAD3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
977 | 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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2023 | RCV000179456.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV001852232.5 |
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
(Oct 27, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000231708.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 3
Sex: mixed
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Likely pathogenic
(Sep 26, 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: SCV000250758.13
First in ClinVar: Oct 11, 2015 Last updated: Oct 05, 2023 |
Comment:
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; … (more)
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; Published in vitro functional studies suggest decreased transcriptional activity; however, it is unknown whether these findings replicate in vivo effect (Stroschein et al., 1999; Fleming et al., 2013); This variant is associated with the following publications: (PMID: 10092624, 23139211, 25944730, 21949838, 29907982, 32123317) (less)
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Pathogenic
(Jan 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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Invitae
Accession: SCV002131323.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 268 of the SMAD3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 268 of the SMAD3 protein (p.Arg268Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 198187). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMAD3 function (PMID: 10092624). This variant disrupts the p.Arg268 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25944730, 26854089; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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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: SCV001808492.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely pathogenic
(-)
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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: SCV001964192.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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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 |
Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing. | Schubert JA | American journal of medical genetics. Part A | 2016 | PMID: 26854089 |
Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. | Wooderchak-Donahue W | American journal of medical genetics. Part A | 2015 | PMID: 25944730 |
SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. | Fleming NI | Cancer research | 2013 | PMID: 23139211 |
Mutations in protein-binding hot-spots on the hub protein Smad3 differentially affect its protein interactions and Smad3-regulated gene expression. | Schiro MM | PloS one | 2011 | PMID: 21949838 |
Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhibitor-1 promoter mediates transforming growth factor beta-induced smad-dependent transcriptional activation. | Stroschein SL | The Journal of biological chemistry | 1999 | PMID: 10092624 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMAD3 | - | - | - | - |
Text-mined citations for rs794727798 ...
HelpRecord last updated Feb 28, 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.