ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.871C>T (p.His291Tyr) (rs863224733)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197016 SCV000254847 uncertain significance Juvenile polyposis syndrome 2015-03-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 291 of the SMAD4 protein (p.His291Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant has not been published in the literature and is not present in population databases. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000481584 SCV000567151 uncertain significance not provided 2015-07-13 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.871C>T at the cDNA level, p.His291Tyr (H291Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 His291Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SMAD4 His291Tyr occurs at a position that is conserved across species and is located in the SAD region (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether SMAD4 His291Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562150 SCV000675138 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)

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