ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1498A>G (p.Ile500Val) (rs281875322)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624818 SCV000741420 pathogenic Inborn genetic diseases 2016-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000059733 SCV000706695 pathogenic not provided 2017-03-16 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000023061 SCV000803811 pathogenic Myhre syndrome 2017-12-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763031 SCV000893500 pathogenic Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000059733 SCV000211666 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The I500V variant in the SMAD4 gene has been reported previously in association with Myhre syndrome and affects a known mutational hotspot in the gene (Le Goff et al., 2011; Caputo et al., 2012; Lin et al., 2016). Additionally, studies in a fibroblast cell line from a patient with the I500V variant show that this variant impacts the function of the protein (Piccolo et al., 2014). The I500V variant is observed in 1/111702 (0.0009%) alleles from an individual of non-Finnish European background in large population cohorts (Lek et al., 2016). The I500V variant is a conservative amino acid substitution which occurs at a position that is conserved across species. We interpret I500V as a pathogenic variant.
GeneReviews RCV000023061 SCV000564086 pathogenic Myhre syndrome 2017-01-31 no assertion criteria provided literature only
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000023061 SCV000746947 pathogenic Myhre syndrome 2017-12-18 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000635427 SCV000840072 pathogenic Juvenile polyposis syndrome 2018-04-27 criteria provided, single submitter clinical testing SMAD4, c.1498A>G, p.Ile500Val The c.1498A>G (p. Ile500Val) variant in the SMAD4 gene has been reported in multiple individuals with MYRHE syndrome (PMID 22158539, 22243968, 22585601, 24398790, 26636501, 27302097). This variant is observed with an ultra-low minor allele frequency in the gnomAD database (1/246232). This variant is on a known mutation hot spot with another pathogenic variant p.Ile500Thr. Functional studies on this variant suggested increased SMAD4 protein levels and increased TGF-beta signaling (PMID 24398790). Therefore, the c.1498A>G (p. Ile500Val) variant in the SMAD4 gene is classified as pathogenic
Invitae RCV000635427 SCV000756840 pathogenic Juvenile polyposis syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 500 of the SMAD4 protein (p.Ile500Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in several individuals affected with Myhre syndrome and has been described as a common cause of the disease (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097). ClinVar contains an entry for this variant (Variation ID: 30150). Experimental studies using patient-derived fibroblasts have shown that this missense change results in increased SMAD4 protein expression and activation of TGF-β signaling, suggesting a gain-of-function (PMID: 24398790). The p.Ile500 amino acid residue in SMAD4 has been determined to be clinically significant (PMID: 22158539, 22243968, 22683461). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab),CHU de Nantes RCV000059733 SCV000778276 pathogenic not provided 2017-07-31 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000059733 SCV000692039 pathogenic not provided no assertion criteria provided clinical testing
OMIM RCV000023061 SCV000044352 pathogenic Myhre syndrome 2012-06-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000059733 SCV000091303 not provided not provided no assertion provided not provided
Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale) RCV000023061 SCV000106023 pathogenic Myhre syndrome no assertion criteria provided not provided Converted during submission to Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.