ClinVar Miner

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

dbSNP: rs377767327
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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.
Ambry Genetics RCV002326681 SCV002630803 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2020-03-18 criteria provided, single submitter clinical testing The c.425-6A>G intronic variant results from an A to G substitution 6 nucleotides upstream from coding exon 3 in the SMAD4 gene. This intronic variant has been reported in an individual who was diagnosed with JPS syndrome at age 10 and had several colonic and gastric polys through the age of 34 when last evaluated (Aretz S et al. J. Med. Genet. 2007 Nov;44:702-9). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003595857 SCV004297846 likely pathogenic Juvenile polyposis syndrome 2023-12-22 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the SMAD4 gene. It does not directly change the encoded amino acid sequence of the SMAD4 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of juvenile polyposis syndrome (PMID: 17873119; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24803). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.