ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1082G>A (p.Arg361His) (rs377767347)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567057 SCV000676263 pathogenic Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
Database of Curated Mutations (DoCM) RCV000419206 SCV000504618 likely pathogenic Uterine cervical neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431203 SCV000504619 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441473 SCV000504620 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423753 SCV000504621 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434006 SCV000504622 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439037 SCV000504623 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421390 SCV000504624 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431590 SCV000504625 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Fulgent Genetics,Fulgent Genetics RCV000763030 SCV000893499 pathogenic Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000520995 SCV000617741 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted SMAD4 c.1082G>A at the cDNA level, p.Arg361His (R361H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been reported in several individuals with Juvenile Polyposis syndrome, some also having a diagnosis of Hereditary Hemorrhagic Telangiectasia (Kim 2000, Gallione 2010, Schwenter 2012, Wain 2014). SMAD4 Arg361His was shown to inhibit binding of SMAD4 to SMAD2, and was shown in a reporter assay to abolish the ability of SMAD4 to down regulate c-myc in a TGF-beta-dependent manner (Wu 2001, Lim 2006). SMAD4 Arg361His was not observed in large population cohorts (Lek 2016). This variant is located in the MH2 domain (Howe 2004, Aretz 2007, Calva-Cerqueria 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000635423 SCV000756836 pathogenic Juvenile polyposis syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 361 of the SMAD4 protein (p.Arg361His). 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 been reported in several individuals with juvenile polyposis syndrome (JPS), hereditary hemorrhagic telangiectasia (HHT) and a combined syndrome including features of both diseases (JPHT) (PMID: 10797267, 17873119, 20101697, 22331366). ClinVar contains an entry for this variant (Variation ID: 24832). Experimental studies have shown that this missense change abolishes the interaction of the Smad4 protein with other R-Smads, disrupting the formation of a functional heterocomplex (PMID: 15014009, 27595937). A different missense substitution at this codon (p.Arg361Cys) has been determined to be pathogenic (PMID: 9811934, 16613914, 10764709, 17873119, 20101697). This suggests that the arginine residue is critical for SMAD4 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV000021712 SCV000042378 pathogenic JP and JP/HHT 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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