ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1081C>G (p.Arg361Gly) (rs80338963)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000635431 SCV000756844 likely pathogenic Juvenile polyposis syndrome 2017-12-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 361 of the SMAD4 protein (p.Arg361Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with a SMAD4-related disease and in an additional individual affected with juvenile polyposis (PMID: 15031030, 18823382). ClinVar contains an entry for this variant (Variation ID: 24830). 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. Two additional missense substitutions at this codon (p.Arg361Cys, p.Arg361His) have been determined to be pathogenic (PMID: 9811934, 17873119, 20101697, 27595937). This suggests that the arginine residue is critical for SMAD4 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Research and Development, ARUP Laboratories RCV000021710 SCV000042376 pathogenic JP and JP/HHT 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000425278 SCV000507402 likely pathogenic Uterine cervical neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436432 SCV000507403 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418748 SCV000507404 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428136 SCV000507405 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438396 SCV000507406 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418132 SCV000507407 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428393 SCV000507408 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441273 SCV000507409 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only

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