ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.153dup (p.Asp52fs)

dbSNP: 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 RCV002312693 SCV000217743 pathogenic Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2016-02-16 criteria provided, single submitter clinical testing The c.153dupA pathogenic mutation, located in coding exon 1 of the SMAD4 gene, results from a duplication of A at nucleotide position 153, causing a translational frameshift with a predicted alternate stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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 2023-07-17 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. Loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 187217). For these reasons, this variant has been classified as Pathogenic.

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