ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1259G>A (p.Arg420His) (rs1064793725)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574816 SCV000675132 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000480803 SCV000566870 uncertain significance not provided 2015-06-10 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.1259G>A at the cDNA level, p.Arg420His (R420H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Although this variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism, it has been observed as a confirmed somatic mutation in lung cancer (COSMIC, Yanagisawa 2000, Wu 2001). Functional assays of somatic SMAD4 Arg420His have indicated that this variant may impair transactivation and result in an inability to form appropriate hetero-oligomer complexes but results have been inconsistent (Yanagisawa 2000, Wu 2001). SMAD4 Arg420His 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 Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Arg420His occurs at a position that is conserved and is located within the MH2 domain (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 Arg420His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000701615 SCV000830425 uncertain significance Juvenile polyposis syndrome 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 420 of the SMAD4 protein (p.Arg420His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. 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: 419212). Experimental studies indicate that this missense change has no effect on SMAD2 protein function (PMID: 15014009). 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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