Previously reported pathogenic variant, de novo in this case with maternity and paternity confirmed (PS2).
ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.1499T>C (p.Ile500Thr)
Germline
Classification
Help
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.
(11)
Help
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005359.6(SMAD4):c.1499T>C (p.Ile500Thr)
Variation ID: 30149 Accession: VCV000030149.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q21.2 18: 51078307 (GRCh38) [ NCBI UCSC ] 18: 48604677 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 31, 2013 Sep 29, 2024 Jul 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005359.6:c.1499T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005350.1:p.Ile500Thr missense NC_000018.10:g.51078307T>C NC_000018.9:g.48604677T>C NG_013013.2:g.115268T>C LRG_318:g.115268T>C LRG_318t1:c.1499T>C LRG_318p1:p.Ile500Thr Q13485:p.Ile500Thr - Protein change
- I500T
- Other names
- -
- Canonical SPDI
- NC_000018.10:51078306:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| SMAD4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2160 | 2202 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jul 13, 2022 | RCV000023060.20 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Jul 3, 2024 | RCV000059734.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 25, 2021 | RCV001852006.12 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 26, 2017)
|
criteria provided, single submitter
Method: research
|
Myhre syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Study: Broad Institute Center for Mendelian Genomics (CMG)
Accession: SCV000693905.1 First in ClinVar: Nov 23, 2017 Last updated: Nov 23, 2017 |
Comment:
Previously reported pathogenic variant, de novo in this case with maternity and paternity confirmed (PS2).
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
|
|
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Pathogenic
(May 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Myhre syndrome
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429395.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Myhre syndrome
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570393.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
This SMAD4 variant (rs281875321) is absent from a large population dataset and has been reported in ClinVar. This missense change has been identified in multiple … (more)
This SMAD4 variant (rs281875321) is absent from a large population dataset and has been reported in ClinVar. This missense change has been identified in multiple unrelated individuals with Myhre syndrome. Ile500 lies in the MAD homology 2 (MH2) domain, a region at the C-terminus of the protein, which is required for TGF-beta/BMP signal transduction. Experiments using cultured skin fibroblasts from a patient with the p.Ile500Thr substitution showed decreased levels of SMAD4 ubiquitination with increased levels of SMAD4 protein, enhanced levels of phosphorylated SMAD2/3 and SMAD1/5/8 proteins, and decreased mRNA levels of downstream TGF-beta and BMP target genes compared to controls. This variant was not detected in specimens provided by the patient's mother and father and is apparently de novo. We consider c.1499T>C to be pathogenic. (less)
|
|
|
Pathogenic
(Mar 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002157123.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this variant affects SMAD4 protein function (PMID: 31654632, 22158539). This variant has been observed in individual(s) with Myhre syndrome (PMID: … (more)
Experimental studies have shown that this variant affects SMAD4 protein function (PMID: 31654632, 22158539). This variant has been observed in individual(s) with Myhre syndrome (PMID: 22158539, 27302097, 30921096, 24424121, 22243968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30149). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 500 of the SMAD4 protein (p.Ile500Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant disrupts the p.Ile500 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097, 24398790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617742.2
First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: significantly increased transcription activity compared to wild type … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: significantly increased transcription activity compared to wild type (PMID: 31654632); 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: 22158539, 22585601, 27562837, 22243968, 27302097, 24424121, 24398790, 22683461, 24580733, 24715504, 11977156, 25252769, 30921096, 32917212, 35907855, 33057194, 35982159, 31654632, 17873119, 18823382, 15235019) (less)
|
|
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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Myhre syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058786.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 22243968, PS2_S). Same nucleotide change resulting in same amino acid … (more)
The variant has been previously reported as de novo in a similarly affected individual (PMID: 22243968, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030149, PMID:2215 8539, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.776, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030150, PMID:22158539,22158539, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Clinodactyly of the 5th toe (present) , Abnormal facial shape (present) , Hearing impairment (present) , Intellectual disability (present) , Fetal growth restriction (present) , … (more)
Clinodactyly of the 5th toe (present) , Abnormal facial shape (present) , Hearing impairment (present) , Intellectual disability (present) , Fetal growth restriction (present) , Lymphedema (present) , Overweight (present) , Pericardial effusion (present) , Mild short stature (present) , Abnormal heart valve morphology (present) , Visual impairment (present) (less)
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pathogenic
(-)
|
no assertion criteria provided
Method: not provided
|
Myhre syndrome
Affected status: not provided
Allele origin:
unknown
|
Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale)
Accession: SCV000106024.1
First in ClinVar: Nov 21, 2013 Last updated: Nov 21, 2013 |
Comment:
Converted during submission to Pathogenic.
|
|
|
Pathogenic
(Jun 01, 2012)
|
no assertion criteria provided
Method: literature only
|
MYHRE SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044351.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 23, 2017 |
Comment on evidence:
In 5 unrelated patients with sporadic occurrence of Myhre syndrome (MYHRS; 139210), Le Goff et al. (2012) identified a de novo heterozygous 1499T-C transition in … (more)
In 5 unrelated patients with sporadic occurrence of Myhre syndrome (MYHRS; 139210), Le Goff et al. (2012) identified a de novo heterozygous 1499T-C transition in the SMAD4 gene, resulting in an ile500-to-thr (I500T) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. The same residue was mutated in other patients with the disorder (I500V, 600993.0016 and I500M, 600993.0017). Studies of fibroblasts from 2 patients with the I500T mutation showed enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls, suggesting stabilization of the mutant protein. Since SMAD4 has a pivotal role in TGF-beta and BMP signaling, Le Goff et al. (2012) analyzed the level of phosphorylation of other SMAD proteins. There was an 8-fold increase in phosphorylated SMAD2 (601366) and SMAD3 (603109), and an 11-fold increase in phosphorylated SMAD1 (601595), SMAD5 (603110), and SMAD8 (603295) in cell nuclei compared to controls. The mutant SMAD4-containing complexes were associated with decreased mRNA levels of downstream TGF-beta and variable effects on BMP targets. Caputo et al. (2012) identified a heterozygous de novo I500T mutation in 3 unrelated patients with Myhre syndrome. In a woman with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by Lindor et al. (2002), Lindor et al. (2012) identified heterozygosity for the I500T mutation in the SMAD4 gene. The patient had chronically restrictive indices on echocardiography despite having undergone pericardiectomy, and required repeated procedures to address recurrent laryngotracheal stenoses. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692040.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
UniProtKB/Swiss-Prot
Accession: SCV000091304.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Myhre syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000564087.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This SMAD4 variant (rs281875321) is absent from a large population dataset and has been reported in ClinVar. This missense change has been identified in multiple unrelated individuals with Myhre syndrome. Ile500 lies in the MAD homology 2 (MH2) domain, a region at the C-terminus of the protein, which is required for TGF-beta/BMP signal transduction. Experiments using cultured skin fibroblasts from a patient with the p.Ile500Thr substitution showed decreased levels of SMAD4 ubiquitination with increased levels of SMAD4 protein, enhanced levels of phosphorylated SMAD2/3 and SMAD1/5/8 proteins, and decreased mRNA levels of downstream TGF-beta and BMP target genes compared to controls. This variant was not detected in specimens provided by the patient's mother and father and is apparently de novo. We consider c.1499T>C to be pathogenic.
Comment:
Experimental studies have shown that this variant affects SMAD4 protein function (PMID: 31654632, 22158539). This variant has been observed in individual(s) with Myhre syndrome (PMID: 22158539, 27302097, 30921096, 24424121, 22243968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30149). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 500 of the SMAD4 protein (p.Ile500Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant disrupts the p.Ile500 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097, 24398790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: significantly increased transcription activity compared to wild type (PMID: 31654632); 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: 22158539, 22585601, 27562837, 22243968, 27302097, 24424121, 24398790, 22683461, 24580733, 24715504, 11977156, 25252769, 30921096, 32917212, 35907855, 33057194, 35982159, 31654632, 17873119, 18823382, 15235019)
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 22243968, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030149, PMID:2215 8539, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.776, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030150, PMID:22158539,22158539, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Converted during submission to Pathogenic.
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. |
Comment:
Previously reported pathogenic variant, de novo in this case with maternity and paternity confirmed (PS2).
Comment:
This SMAD4 variant (rs281875321) is absent from a large population dataset and has been reported in ClinVar. This missense change has been identified in multiple unrelated individuals with Myhre syndrome. Ile500 lies in the MAD homology 2 (MH2) domain, a region at the C-terminus of the protein, which is required for TGF-beta/BMP signal transduction. Experiments using cultured skin fibroblasts from a patient with the p.Ile500Thr substitution showed decreased levels of SMAD4 ubiquitination with increased levels of SMAD4 protein, enhanced levels of phosphorylated SMAD2/3 and SMAD1/5/8 proteins, and decreased mRNA levels of downstream TGF-beta and BMP target genes compared to controls. This variant was not detected in specimens provided by the patient's mother and father and is apparently de novo. We consider c.1499T>C to be pathogenic.
Comment:
Experimental studies have shown that this variant affects SMAD4 protein function (PMID: 31654632, 22158539). This variant has been observed in individual(s) with Myhre syndrome (PMID: 22158539, 27302097, 30921096, 24424121, 22243968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30149). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 500 of the SMAD4 protein (p.Ile500Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant disrupts the p.Ile500 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097, 24398790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: significantly increased transcription activity compared to wild type (PMID: 31654632); 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: 22158539, 22585601, 27562837, 22243968, 27302097, 24424121, 24398790, 22683461, 24580733, 24715504, 11977156, 25252769, 30921096, 32917212, 35907855, 33057194, 35982159, 31654632, 17873119, 18823382, 15235019)
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 22243968, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030149, PMID:2215 8539, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.776, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030150, PMID:22158539,22158539, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Myhre Syndrome. | Adam MP | - | 2022 | PMID: 28406602 |
| The first two Chinese Myhre syndrome patients with the recurrent SMAD4 pathogenic variants: Functional consequences and clinical diversity. | Li H | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 31654632 |
| Myhre syndrome: a report of six Chinese patients and literature review. | Yu KP | Clinical dysmorphology | 2019 | PMID: 30921096 |
| Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome. | Lin AE | American journal of medical genetics. Part A | 2016 | PMID: 27302097 |
| Severe constipation in a patient with Myhre syndrome: a case report. | Bassett JK | Clinical dysmorphology | 2016 | PMID: 26636501 |
| Myhre and LAPS syndromes: clinical and molecular review of 32 patients. | Michot C | European journal of human genetics : EJHG | 2014 | PMID: 24424121 |
| SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. | Piccolo P | European journal of human genetics : EJHG | 2014 | PMID: 24398790 |
| Mutations of SMAD4 account for both LAPS and Myhre syndromes. | Lindor NM | American journal of medical genetics. Part A | 2012 | PMID: 22585601 |
| A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. | Caputo V | American journal of human genetics | 2012 | PMID: 22243968 |
| Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. | Le Goff C | Nature genetics | 2011 | PMID: 22158539 |
| Confirmation of existence of a new syndrome: LAPS syndrome. | Lindor NM | American journal of medical genetics | 2002 | PMID: 11977156 |
| A new growth deficiency syndrome. | Myhre SA | Clinical genetics | 1981 | PMID: 7296942 |
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Text-mined citations for rs281875321 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.