ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.332A>C (p.His111Pro) (rs1064794363)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000482083 SCV000884548 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing
Color RCV000776540 SCV000912142 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000482083 SCV000568957 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.332A>C at the cDNA level, p.His111Pro (H111P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 His111Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SMAD4 His111Pro occurs at a position that is conserved across species and is located within the MH1 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether SMAD4 His111Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000635412 SCV000756825 uncertain significance Juvenile polyposis syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 111 of the SMAD4 protein (p.His111Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. 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: 420231). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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.