ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.728_735delGGCCTCAG (p.Gly243Alafs) (rs1060500742)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481914 SCV000567314 pathogenic not provided 2015-07-20 criteria provided, single submitter clinical testing The c.728_735delGGCCTCAG deletion in the SMAD4 gene has been reported previouslyin two patients with combined juvenile polyposis syndrome and hereditary hemorrhagictelangiectasia (Schwenter et al., 2012). This deletion causes a frameshift starting withcodon Glycine 243, changes this amino acid to an Alanine residue and creates a prematureStop codon at position 18 of the new reading frame, denoted p.Gly243AlafsX18. It ispredicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. Therefore, we consider the c.728_735delGGCCTCAG deletion in SMAD4 to be a pathogenic variant.
Invitae RCV000470842 SCV000543755 pathogenic Juvenile polyposis syndrome 2017-05-04 criteria provided, single submitter clinical testing This sequence change deletes 8 nucleotides from exon 6 of the SMAD4 mRNA (c.728_735del), causing a frameshift at codon 243. This creates a premature translational stop signal (p.Gly243Alafs*18) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD4 are known to be pathogenic. This particular variant has been reported in individuals affected with an overlapping spectrum of juvenile polyposis and hereditary hemorrhagic telangiectasia (PMID: 22331366). It is also known as c.724_731delTCAGGGCC in the literature. For these reasons, this variant has been classified as Pathogenic.

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