ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.268C>T (p.Arg90Cys)
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.
Likely pathogenic(3); 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.268C>T (p.Arg90Cys)
Variation ID: 426202 Accession: VCV000426202.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67164956 (GRCh38) [ NCBI UCSC ] 15: 67457294 (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 May 22, 2017 Apr 20, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005902.4:c.268C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005893.1:p.Arg90Cys missense NM_001145102.2:c.-48C>T 5 prime UTR NM_001145103.2:c.136C>T NP_001138575.1:p.Arg46Cys missense NC_000015.10:g.67164956C>T NC_000015.9:g.67457294C>T NG_011990.1:g.104100C>T - Protein change
- R90C, R46C
- Other names
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- Canonical SPDI
- NC_000015.10:67164955: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
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
1022 | 1085 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jun 12, 2019 | RCV000489620.2 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV000534111.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jul 19, 2023 | RCV001117316.5 |
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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Uncertain significance
(Jul 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Aneurysm-osteoarthritis syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001275492.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Observation 1: Observation 2: |
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Uncertain significance
(Jun 12, 2019)
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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: SCV000576587.4
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Comment:
Has been reported as a variant of uncertain significance in a 32 year-old male referred for aortopathy genetic testing (Wooderchak-Donahue et al., 2015), and in … (more)
Has been reported as a variant of uncertain significance in a 32 year-old male referred for aortopathy genetic testing (Wooderchak-Donahue et al., 2015), and in an individual with an aortic event at age 42 years (Hostetler et al., 2019).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 426202; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25944730, 00000, 30661052) (less)
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Likely pathogenic
(Sep 25, 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: SCV000658878.7
First in ClinVar: Dec 26, 2017 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 90 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 90 of the SMAD3 protein (p.Arg90Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 25944730, 30661052; Invitae). ClinVar contains an entry for this variant (Variation ID: 426202). 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 SMAD3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(May 18, 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: SCV004362306.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 90 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 90 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in seven unrelated individuals affected with thoracic aortic aneurysm and dissection or other SMAD3-related conditions (PMID: 30661052, 25944730, ClinVar SCV000658878.6, SCV000576587.4, doi:10.13140/2.1.3820.7683). A first degree family member of one of the probands was also reported to be an affected carrier (ClinVar SCV000658878.6). This variant has been identified in 1/251404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg90His and p.Arg90dup, have also been reported in individuals affected with thoracic aortic aneurysm and dissection or related conditions (PMID: 29510914, 32154675, ClinVar RCV000246998.2), indicating 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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Likely Pathogenic
(Jul 19, 2023)
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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: SCV004833996.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 90 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 90 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in seven unrelated individuals affected with thoracic aortic aneurysm and dissection or other SMAD3-related conditions (PMID: 30661052, 25944730, ClinVar SCV000658878.6, SCV000576587.4, doi:10.13140/2.1.3820.7683). A first degree family member of one of the probands was also reported to be an affected carrier (ClinVar SCV000658878.6). This variant has been identified in 1/251404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg90His and p.Arg90dup, have also been reported in individuals affected with thoracic aortic aneurysm and dissection or related conditions (PMID: 29510914, 32154675, ClinVar RCV000246998.2), indicating 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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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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Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature. | Chesneau B | Molecular genetics & genomic medicine | 2020 | PMID: 32154675 |
SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium. | Hostetler EM | Journal of medical genetics | 2019 | PMID: 30661052 |
Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center. | Hicks KL | Journal of vascular surgery | 2018 | PMID: 29510914 |
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 |
[Treatment of herpes simplex]. | - | Fortschritte der Medizin | 1978 | PMID: 658878 |
[Educational system to meet the needs of future medical practice]. | Yatani R | [Kango kyoiku] Japanese journal of nurses' education | 1978 | PMID: 246998 |
Central dopaminergic and noradrenergic components of bromocryptine-induced locomotor activity in mice [proceedings]. | Dolphin AC | British journal of pharmacology | 1977 | PMID: 576587 |
Text-mined citations for rs1085307496 ...
HelpRecord last updated Apr 20, 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.