ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.220C>T (p.Arg74Trp)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005902.4(SMAD3):c.220C>T (p.Arg74Trp)
Variation ID: 502012 Accession: VCV000502012.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67457246 (GRCh37) [ NCBI UCSC ] 15: 67164908 (GRCh38) [ 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 2, 2018 Apr 20, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005902.4:c.220C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005893.1:p.Arg74Trp missense NM_001145102.2:c.-96C>T 5 prime UTR NM_001145103.2:c.88C>T NP_001138575.1:p.Arg30Trp missense NC_000015.10:g.67164908C>T NC_000015.9:g.67457246C>T NG_011990.1:g.104052C>T - Protein change
- R74W, R30W
- Other names
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- Canonical SPDI
- NC_000015.10:67164907: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
1025 | 1089 |
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2022 | RCV000591279.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 12, 2023 | RCV000697102.12 | |
not provided (1) |
no classification provided
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- | RCV000844981.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV004002466.2 |
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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Likely pathogenic
(Oct 12, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001343376.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 74 in the MH1 DNA binding domain of the SMAD3 protein. Computational prediction suggests that this … (more)
This missense variant replaces arginine with tryptophan at codon 74 in the MH1 DNA binding domain of the SMAD3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not alter SMAD3 protein expression levels, but does cause decreased cell survival and lack of downstream target gene expression (PMID: 34434896). This variant has been reported in two individuals affected with Loeys-Dietz syndrome (PMID: 31096651; communication with an external laboratory; ClinVar SCV000825693.5), in an individual affected with familial thoracic aortic dissection and aneurysm (PMID: 29510914), and in an individual affected with isolated thoracic aortic dissection and aneurysm (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg74Gln, is considered to be disease-causing (ClinVar variation ID: 623872), suggesting that arginine at this position is important for SMAD3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Uncertain significance
(May 17, 2017)
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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: SCV000708602.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Jun 01, 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: SCV001812607.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in an individual with TAAD and an individual with features of Loeys-Dietz syndrome type 3 (LDS3) who also harbored an additional cardiogenetic variant in … (more)
Observed in an individual with TAAD and an individual with features of Loeys-Dietz syndrome type 3 (LDS3) who also harbored an additional cardiogenetic variant in the published literature (Hicks et al., 2018; Richter et al., 2019); 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: 31096651, 29510914) (less)
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Pathogenic
(Aug 17, 2023)
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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: SCV000825693.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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: 502012). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 29510914, 31096651; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 74 of the SMAD3 protein (p.Arg74Trp). (less)
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Likely Pathogenic
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Aneurysm-osteoarthritis syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004815329.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with tryptophan at codon 74 in the MH1 DNA binding domain of the SMAD3 protein. Computational prediction suggests that this … (more)
This missense variant replaces arginine with tryptophan at codon 74 in the MH1 DNA binding domain of the SMAD3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not alter SMAD3 protein expression levels, but does cause decreased cell survival and lack of downstream target gene expression (PMID: 34434896). This variant has been reported in two individuals affected with Loeys-Dietz syndrome (PMID: 31096651; communication with an external laboratory; ClinVar SCV000825693.5), in an individual affected with familial thoracic aortic dissection and aneurysm (PMID: 29510914), and in an individual affected with isolated thoracic aortic dissection and aneurysm (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg74Gln, is considered to be disease-causing (ClinVar variation ID: 623872), suggesting that arginine at this position is important for SMAD3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: phenotyping only
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SMAD3-Related Disorder
Affected status: unknown
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV000986808.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as Uncertain significance and reported on 10/21/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpretted as Uncertain significance and reported on 10/21/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Overgrowth (present) , Tall stature (present) , Conductive hearing impairment (present) , Sensorineural hearing loss (present) , Hearing impairment (present) , Hyperacusis (present) , Abnormality … (more)
Overgrowth (present) , Tall stature (present) , Conductive hearing impairment (present) , Sensorineural hearing loss (present) , Hearing impairment (present) , Hyperacusis (present) , Abnormality of the curvature of the vertebral column (present) , Joint hypermobility (present) , Pectus excavatum (present) , Cardiomyopathy (present) , Abnormality of the stomach (present) , Gastrointestinal dysmotility (present) , Oral herpes (present) , Abnormality of primary teeth (present) , Misalignment of teeth (present) (less)
Age: 10-19 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-10-21
Testing laboratory interpretation: Uncertain significance
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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 Key Genes Mutations Associated With the Radiosensitivity by Whole Exome Sequencing in Pancreatic Cancer. | Hu B | Frontiers in oncology | 2021 | PMID: 34434896 |
Genomic Observations of a Rare/Pathogenic SMAD3 Variant in Loeys⁻Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigations. | Richter JE Jr | Medicina (Kaunas, Lithuania) | 2019 | PMID: 31096651 |
Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center. | Hicks KL | Journal of vascular surgery | 2018 | PMID: 29510914 |
[Radiation therapy of malignant melanoma (author's transl)]. | Scherer E | Langenbecks Archiv fur Chirurgie | 1976 | PMID: 825693 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMAD3 | - | - | - | - |
Text-mined citations for rs1343295267 ...
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.