ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1447+2T>C (rs1060500740)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469223 SCV000543752 likely pathogenic Juvenile polyposis syndrome 2018-03-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the SMAD4 gene, which is the last intron. It is expected to disrupt mRNA splicing, however, it is not anticipated to result in nonsense mediated decay. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in an individual with a SMAD4-related disease. However, it has been shown to segregate with disease in a single family with juvenile polyposis syndrome (Invitae database). ClinVar contains an entry for this variant (Variation ID: 405497). A different sequence change that also affects the donor splice site of intron 11 (c.1447+1G>A) was reported in an individual affected with juvenile polyposis syndrome (PMID: 16436638), and a family with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia (PMID: 21572342). In summary, this variant is a rare donor splice site change that has been shown to segregate with juvenile polyposis in a single family. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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