ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1239C>A (p.Tyr413Ter)

dbSNP: rs730881954
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160963 SCV000211672 pathogenic not provided 2014-09-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted SMAD4 c.1239C>A at the cDNA level and p.Tyr413Ter (Y413X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this specific variant has not, to our knowledge, been reported in the literature, a different nucleotide substitution leading to the same truncating variant has been published in a Juvenile Polyposis Syndrome family (Jee 2013). We consider SMAD4 Tyr413Ter to be pathogenic.
Invitae RCV001850275 SCV002227805 pathogenic Juvenile polyposis syndrome 2021-09-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 182871). This premature translational stop signal has been observed in individual(s) with clinical features of juvenile polyposis syndrome (PMID: 24312718, 26681312). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr413*) in the SMAD4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475).

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