ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.1268G>A (p.Ser423Asn)
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.1268G>A (p.Ser423Asn)
Variation ID: 449264 Accession: VCV000449264.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67190526 (GRCh38) [ NCBI UCSC ] 15: 67482864 (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 Dec 19, 2017 Feb 20, 2024 Sep 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005902.4:c.1268G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005893.1:p.Ser423Asn missense NM_001145102.2:c.953G>A NP_001138574.1:p.Ser318Asn missense NM_001145103.2:c.1136G>A NP_001138575.1:p.Ser379Asn missense NM_001145104.2:c.683G>A NP_001138576.1:p.Ser228Asn missense NC_000015.10:g.67190526G>A NC_000015.9:g.67482864G>A NG_011990.1:g.129670G>A - Protein change
- S423N, S228N, S318N, S379N
- Other names
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- Canonical SPDI
- NC_000015.10:67190525: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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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2017 | RCV000521706.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 6, 2021 | RCV002251486.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2022 | RCV001347590.8 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Sep 15, 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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GeneDx
Accession: SCV000617169.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The S423N variant that is likely pathogenic was identified in the SMAD3 gene. It has not been published as pathogenic or been reported as benign … (more)
The S423N variant that is likely pathogenic was identified in the SMAD3 gene. It has not been published as pathogenic or been reported as benign to our knowledge. Based on targeted family studies, it has been determined that the S423N variant occurred de novo in an affected individual who underwent TAAD, Marfan syndrome, and Related Disorders genetic testing at GeneDx. The S423N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the S423N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (S423G) has been reported in the Human Gene Mutation Database in association with AOS (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined. (less)
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Likely pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 3
Affected status: yes
Allele origin:
germline
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National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV002522193.2
First in ClinVar: Jun 05, 2022 Last updated: Oct 07, 2023 |
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Uncertain significance
(Mar 02, 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: SCV002682593.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.S423N variant (also known as c.1268G>A), located in coding exon 9 of the SMAD3 gene, results from a G to A substitution at nucleotide … (more)
The p.S423N variant (also known as c.1268G>A), located in coding exon 9 of the SMAD3 gene, results from a G to A substitution at nucleotide position 1268. The serine at codon 423 is replaced by asparagine, an amino acid with highly similar properties, and is located in the MH2 domain. This alteration was reported in association with Loeys-Dietz syndrome (Schepers D et al. Hum. Mutat., 2018 05;39:621-634). Other alterations affecting the same amino acid, p.S423R (c.1269T>G) and p.S423G (c.1267A>G), has been reported in association with SMAD3- related disease (Aubart M et al. PLoS ONE, 2014 May;9:e96387; Zhurayev R et al. Genet Res (Camb), 2016 10;98:e13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Sep 06, 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: SCV001541859.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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 not expected to disrupt SMAD3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 449264). This missense change has been observed in individual(s) with clinical features of Loeys Dietz syndrome (PMID: 29392890). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 423 of the SMAD3 protein (p.Ser423Asn). (less)
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Pathogenic
(Jul 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Aneurysm-osteoarthritis syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767609.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). This variant is found within the MH2 domain (PMID: 29392890). (SP) 0704 - Other missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. An alternative missense variant at the same residue (p.Ser423Arg) has been reported as a VUS and observed in a patient with Marfan syndrome, who had an additional variant in FBN1 (ClinVar, PMID: 27724990). Another missense variant (p.Ser423Gly) has been reported as likely pathogenic in two patients with Marfan-like syndrome and Loeys-Dietz syndrome (PMID: 29392890, PMID: 24804794). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo , in two patients with Loeys-Dietz syndrome and thoracic aortic aneurysms and dissections (ClinVar, PMID: 29392890). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (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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A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. | Schepers D | Human mutation | 2018 | PMID: 29392890 |
Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients. | Zhurayev R | Genetics research | 2016 | PMID: 27724990 |
Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition. | Aubart M | PloS one | 2014 | PMID: 24804794 |
Text-mined citations for rs1555414503 ...
HelpRecord last updated Feb 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.