ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.1082G>A (p.Arg361His)
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_005359.6(SMAD4):c.1082G>A (p.Arg361His)
Variation ID: 24832 Accession: VCV000024832.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 51065549 (GRCh38) [ NCBI UCSC ] 18: 48591919 (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 4, 2013 Feb 14, 2024 Jun 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005359.6:c.1082G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005350.1:p.Arg361His missense NC_000018.10:g.51065549G>A NC_000018.9:g.48591919G>A NG_013013.2:g.102510G>A LRG_318:g.102510G>A LRG_318t1:c.1082G>A LRG_318p1:p.Arg361His Q13485:p.Arg361His - Protein change
- R361H
- Other names
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- Canonical SPDI
- NC_000018.10:51065548: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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SMAD4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2062 | 2104 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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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Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000421390.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000441473.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000423753.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000431590.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000419206.9 | |
Pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000431203.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000434006.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000439037.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 20, 2020 | RCV000520995.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 22, 2022 | RCV000635423.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763030.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2021 | RCV002316201.8 | |
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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
Help
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
Help
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
Help
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 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myhre syndrome
Juvenile polyposis syndrome Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Carcinoma of pancreas
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893499.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Nov 20, 2020)
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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: SCV000617741.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
Published functional studies demonstrate a damaging effect: inhibition of SMAD2 binding and defective down regulation of c-myc in a TGF-beta-dependent manner (Wu 2001, Lim 2006); … (more)
Published functional studies demonstrate a damaging effect: inhibition of SMAD2 binding and defective down regulation of c-myc in a TGF-beta-dependent manner (Wu 2001, Lim 2006); Not observed in large population cohorts (Lek 2016); 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: 26046389, 10340381, 22331366, 10797267, 11274206, 27595937, 23139211, 24525918, 17873119, 20101697, 17132729, 28693246, 32300199) (less)
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Pathogenic
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103775.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: SMAD4 c.1082G>A (p.Arg361His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SMAD4 c.1082G>A (p.Arg361His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251392 control chromosomes. c.1082G>A has been reported in the literature in individuals affected with Juvenile Polyposis Syndrome or hereditary hemorrhagic telangiectasia. These data indicate that the variant is associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000756836.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg361 amino acid residue in SMAD4. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg361 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9811934, 10764709, 16613914, 17873119, 20101697). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 15014009, 27595937). 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 SMAD4 protein function. ClinVar contains an entry for this variant (Variation ID: 24832). This missense change has been observed in individuals with juvenile polyposis syndrome (JPS), hereditary hemorrhagic telangiectasia (HHT) and a combined syndrome including features of both diseases (JPHT) (PMID: 10797267, 17873119, 20101697, 22331366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 361 of the SMAD4 protein (p.Arg361His). (less)
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Pathogenic
(Oct 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000676263.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R361H pathogenic mutation (also known as c.1082G>A), located in coding exon 8 of the SMAD4 gene, results from a G to A substitution at … (more)
The p.R361H pathogenic mutation (also known as c.1082G>A), located in coding exon 8 of the SMAD4 gene, results from a G to A substitution at nucleotide position 1082. The arginine at codon 361 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with a clinical diagnosis of juvenile polyposis syndrome (JPS) and several also with a diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Kim IJ et al. Int. J. Cancer, 2000 May;86:529-32; Aretz S et al. J. Med. Genet., 2007 Nov;44:702-9). This mutation was shown through in vitro interaction assays to disrupt Smad2/Smad4 heterocomplex formation (Wu JW et al. J. Biol. Chem., 2001 Jun;276:20688-94). In addition, multiple other alterations at the same codon (p.R361C, p.R361G, p.R361L, p.R361S) have also been described in individuals with clinical JPS as well as combined JPS-HHT (Gallione C et al. Am. J. Med. Genet. A, 2010 Feb;152A:333-9; Houlston R et al. Hum. Mol. Genet., 1998 Nov;7:1907-12; Howe JR et al. J. Med. Genet., 2004 Jul;41:484-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Neoplasm of uterine cervix
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504618.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504619.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504622.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Gastric adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504623.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504620.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Carcinoma of esophagus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504621.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Pancreatic adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504625.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504624.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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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Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). | McDonald J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32300199 |
Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase. | Qu H | Scientific reports | 2016 | PMID: 27595937 |
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. | Schwenter F | Journal of gastroenterology | 2012 | PMID: 22331366 |
Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. | Gallione C | American journal of medical genetics. Part A | 2010 | PMID: 20101697 |
Novel mutations in Smad proteins that inhibit signaling by the transforming growth factor beta in mammalian cells. | Prokova V | Biochemistry | 2007 | PMID: 17994767 |
High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. | Aretz S | Journal of medical genetics | 2007 | PMID: 17873119 |
SMAD4 mutations found in unselected HHT patients. | Gallione CJ | Journal of medical genetics | 2006 | PMID: 16613914 |
The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. | Howe JR | Journal of medical genetics | 2004 | PMID: 15235019 |
A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). | Gallione CJ | Lancet (London, England) | 2004 | PMID: 15031030 |
Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors. | Iacobuzio-Donahue CA | Clinical cancer research : an official journal of the American Association for Cancer Research | 2004 | PMID: 15014009 |
Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells. | De Bosscher K | The Biochemical journal | 2004 | PMID: 14715079 |
Role of Smad4 (DPC4) inactivation in human cancer. | Miyaki M | Biochemical and biophysical research communications | 2003 | PMID: 12821112 |
Formation of a stable heterodimer between Smad2 and Smad4. | Wu JW | The Journal of biological chemistry | 2001 | PMID: 11274206 |
Germline mutations of the dpc4 gene in Korean juvenile polyposis patients. | Kim IJ | International journal of cancer | 2000 | PMID: 10797267 |
Transcriptional control by the TGF-beta/Smad signaling system. | Massagué J | The EMBO journal | 2000 | PMID: 10775259 |
Analysis of genetic and phenotypic heterogeneity in juvenile polyposis. | Woodford-Richens K | Gut | 2000 | PMID: 10764709 |
Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients. | Koyama M | Mutation research | 1999 | PMID: 10479724 |
Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. | Houlston R | Human molecular genetics | 1998 | PMID: 9811934 |
TGF-beta signaling and cancer: structural and functional consequences of mutations in Smads. | Hata A | Molecular medicine today | 1998 | PMID: 9679244 |
Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. | Takagi Y | Gastroenterology | 1996 | PMID: 8898652 |
http://docm.genome.wustl.edu/variants/ENST00000342988:c.1082G>A | - | - | - | - |
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Text-mined citations for rs377767347 ...
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.