ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.425-6A>G (rs377767327)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235856 SCV000293525 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.425-6A>G or IVS3-6A>G and consists of a A>G nucleotide substitution at the -6 position of intron 3 of the SMAD4 gene. This variant has been observed in at least one individual with a clinical diagnosis of juvenile polyposis syndrome (Aretz 2007). SMAD4 c.425-6A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is not conserved across species. Multiple in silico models predict this variant may cause the gain of a cryptic splice acceptor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Therefore, based on currently available information, it is unclear whether SMAD4 c.425-6A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Research and Development, ARUP Laboratories RCV000021683 SCV000042349 pathogenic Juvenile polyposis syndrome 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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