ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1258_1259dup (p.Ala421fs)

dbSNP: rs730881956
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160965 SCV000211674 pathogenic Hereditary cancer-predisposing syndrome 2014-08-21 criteria provided, single submitter clinical testing The c.1259_1260insCG (aka c.1258_1259dupCG) mutation in the SMAD4 gene causes a frameshift starting with codon Alanine 421, changes this amino acid to a Valine residue and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Ala421ValfsX16. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The normal sequence with the bases that are duplicated in braces is: TGGG{CG}TGCA. The variant is found in SMAD4 panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV001052787 SCV001217013 pathogenic Juvenile polyposis syndrome 2022-08-09 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 182873). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala421Valfs*16) 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).

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