ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.153dupA (p.Asp52Argfs) (rs786203560)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166924 SCV000217743 pathogenic Hereditary cancer-predisposing syndrome 2016-02-16 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)
GeneDx RCV000478516 SCV000570745 pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in SMAD4 is denoted c.153dupA at the cDNA level and p.Asp52ArgfsX2 (D52RfsX2) at the protein level. The normal sequence, with the base that is duplicated in braces, is GAAAAA[A]GATG. The duplication causes a frameshift which changes an Aspartic Acid to an Arginine at codon 52, and creates a premature stop codon at position 2 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 either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Invitae RCV000695541 SCV000824048 pathogenic Juvenile polyposis syndrome 2018-06-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp52Argfs*2) in the SMAD4 gene. It is expected to result in an absent or disrupted protein product. 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: 187217). Loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). For these reasons, this variant has been classified as Pathogenic.

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