ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.181A>G (p.Ile61Val) (rs1064794204)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000581125 SCV000686532 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764160 SCV000895162 uncertain significance Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000480772 SCV000568184 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.181A>G at the cDNA level, p.Ile61Val (I61V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. SMAD4 Ile61Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). SMAD4 Ile61Val is located in the MH1 domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether SMAD4 Ile61Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000635474 SCV000756888 uncertain significance Juvenile polyposis syndrome 2018-05-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 61 of the SMAD4 protein (p.Ile61Val). 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 not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 419954). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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