ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.715G>A (p.Glu239Lys)
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.715G>A (p.Glu239Lys)
Variation ID: 30311 Accession: VCV000030311.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67181297 (GRCh38) [ NCBI UCSC ] 15: 67473635 (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 Apr 15, 2024 Jul 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005902.4:c.715G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005893.1:p.Glu239Lys missense NM_001145102.2:c.400G>A NP_001138574.1:p.Glu134Lys missense NM_001145103.2:c.583G>A NP_001138575.1:p.Glu195Lys missense NM_001145104.2:c.130G>A NP_001138576.1:p.Glu44Lys missense NC_000015.10:g.67181297G>A NC_000015.9:g.67473635G>A NG_011990.1:g.120441G>A P84022:p.Glu239Lys - Protein change
- E239K, E195K, E134K, E44K
- Other names
- p.E239K:GAG>AAG
- Canonical SPDI
- NC_000015.10:67181296: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 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Jul 6, 2017 | RCV000023246.4 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2023 | RCV001703421.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 3, 2023 | RCV003528136.1 |
Submissions - Germline
Classification
Help
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
(Jul 06, 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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840070.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
This c.715G>A (p.Glu239Lys) variant in the SMAD3 gene has been reported in multiple patients with thoracic aortic disorders [PMID 21778426, 25644172, 25555948]. Among them, this … (more)
This c.715G>A (p.Glu239Lys) variant in the SMAD3 gene has been reported in multiple patients with thoracic aortic disorders [PMID 21778426, 25644172, 25555948]. Among them, this variant was detected in three affected siblings, all carriers, while another sibling was unaffected and non carrier [PMID 21778426]. This variant is conserved in mammals. While not clinically validated, computer-based algorithms SIFT and Polyphen-2 predict the protein change to be deleterious. It is thus classified as likely pathogenic. (less)
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Likely pathogenic
(Jun 07, 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: SCV000250752.16
First in ClinVar: Oct 11, 2015 Last updated: Jun 17, 2023 |
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with TAAD referred for genetic testing at GeneDx and in the published literature (Regalado et al., … (more)
Observed in multiple unrelated patients from different ethnic backgrounds with TAAD referred for genetic testing at GeneDx and in the published literature (Regalado et al., 2011; Panesi et al., 2015; Campens et al., 2015; Arnaud at al., 2019; Hostetler 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: 25555948, 25644172, 21778426, 28185953, 30661052, 30739908, 35487415, 31447099, 29392890) (less)
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Likely pathogenic
(Jan 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV003917401.7
First in ClinVar: Apr 23, 2023 Last updated: Apr 15, 2024 |
Comment:
SMAD3: PM2, PP1, PP2, PP3, PP4
Number of individuals with the variant: 1
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Likely pathogenic
(Jul 03, 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: SCV004297627.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 239 of the SMAD3 protein (p.Glu239Lys). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 21778426, 25555948, 30739908; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30311). 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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Pathogenic
(Sep 02, 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: SCV000044537.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2014 |
Comment on evidence:
In a small family with 3 sibs affected with thoracic aortic aneurysm and dissection (LDS3; 613795), Regalado et al. (2011) identified a G-to-A transition at … (more)
In a small family with 3 sibs affected with thoracic aortic aneurysm and dissection (LDS3; 613795), Regalado et al. (2011) identified a G-to-A transition at nucleotide 715 in exon 6 of the SMAD3 gene, resulting in a glutamine-to-lysine substitution at codon 239 (E239K). Exon 6 encodes the MH2 protein-protein binding domain. Glu239 is completely conserved from human to Drosophila, and the E239K mutation was predicted to disrupt protein function. The mutation was not identified in 2,300 control exomes. (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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Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). | Arnaud P | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30739908 |
Novel TGFBR2 and known missense SMAD3 mutations: two case reports of thoracic aortic aneurysms. | Panesi P | The Annals of thoracic surgery | 2015 | PMID: 25555948 |
Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. | Regalado ES | Circulation research | 2011 | PMID: 21778426 |
Text-mined citations for rs387906853 ...
HelpRecord last updated Apr 15, 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.