Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000657426 | SCV000779161 | pathogenic | not provided | 2022-08-02 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation, as the last 36 amino acids are replaced with 9 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18823382) |
| Invitae | RCV002228678 | SCV000816532 | pathogenic | Juvenile polyposis syndrome | 2018-10-25 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 156513). For these reasons, this variant has been classified as Pathogenic. A different truncation (p.His530Thrfs*47) that lies downstream of this variant has been determined to be pathogenic (PMID: 18178612, Invitae). This suggests that deletion of this region of the SMAD4 protein is causative of disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SMAD4 gene (p.Ser517Glufs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acids of the SMAD4 protein. |
| Ambry Genetics | RCV002399512 | SCV002705126 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2014-09-08 | criteria provided, single submitter | clinical testing | The c.1547dupA pathogenic mutation, located in coding exon 11 of the SMAD4 gene, results from a duplication of A at nucleotide position 1547, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). |
| Pathway Genomics | RCV000144660 | SCV000189989 | pathogenic | Generalized juvenile polyposis/juvenile polyposis coli | 2014-07-24 | no assertion criteria provided | clinical testing |