ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1333C>T (p.Arg445Ter) (rs377767360)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163892 SCV000214483 pathogenic Hereditary cancer-predisposing syndrome 2018-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000021731 SCV000543757 pathogenic Juvenile polyposis syndrome 2018-05-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 445 (p.Arg445*) of the SMAD4 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs377767360, ExAC 0.002%). Loss-of-function variants in SMAD4 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with juvenile polyposis syndrome (PMID: 10764709, 16152648, 21465659). ClinVar contains an entry for this variant (Variation ID: 24850). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000493396 SCV000582779 pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.1333C>T at the cDNA level and p.Arg445Ter (R445X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with juvenile polyposis syndrome (Woodford-Richens 2000, Handra-Luca 2005, Andrabi 2011) and is considered pathogenic.
Research and Development, ARUP Laboratories RCV000021731 SCV000042397 pathogenic Juvenile polyposis syndrome 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
OMIM RCV000023059 SCV000044350 pathogenic Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2011-05-01 no assertion criteria provided literature only

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