ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1547dupA (p.Ser517Glufs) (rs587783060)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657426 SCV000779161 pathogenic not provided 2017-11-30 criteria provided, single submitter clinical testing This duplication of one nucleotide in SMAD4 is denoted c.1547dupA at the cDNA level and p.Ser517GlufsX10 (S517EfsX10) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AGAC[dupA]GAGC. The duplication causes a frameshift which changes a Serine to a Glutamic Acid at codon 517, and creates a premature stop codon at position 10 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. The last 36 amino acids are replaced by 9 incorrect ones, disrupting a region that contains the MH2 domain and the Glycyl lysine isopeptide (UniProt). We consider this variant to be pathogenic.
Invitae RCV000144660 SCV000816532 pathogenic Juvenile polyposis syndrome 2018-10-25 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SMAD4 gene (p.Ser517Glufs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acids of the SMAD4 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 156513). A different truncation (p.His530Thrfs*47) that lies downstream of this variant has been determined to be pathogenic (PMID: 18178612, Invitae). This suggests that deletion of this region of the SMAD4 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Pathway Genomics RCV000144660 SCV000189989 pathogenic Juvenile polyposis syndrome 2014-07-24 no assertion criteria provided clinical testing

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