Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002310634 | SCV000214483 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2021-08-27 | criteria provided, single submitter | clinical testing | The p.R445* pathogenic mutation (also known as c.1333C>T), located in coding exon 10 of the SMAD4 gene, results from a C to T substitution at nucleotide position 1333. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals with Juvenile Polyposis Syndrome (JPS) (Woodford-Richens K et al. Gut. 2000 May;46:656-60; Heald B et al. Am. J. Med. Genet. A. 2015 Aug;167A:1758-62; Handra-Luca A et al. Am. J. Med. Genet. A. 2005 Oct;138A:113-7). This mutation has also been reported in a patient with lower grade glioma from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun, 2015 Dec;6:10086). Of note, this alteration is also designated as c.1363C>T in published literature. In addition to the clinical data presented in the literature, 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. |
| Labcorp Genetics |
RCV001376567 | SCV000543757 | pathogenic | Juvenile polyposis syndrome | 2023-04-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 24850). This premature translational stop signal has been observed in individual(s) with juvenile polyposis syndrome (PMID: 10764709, 16152648, 21465659). This variant is present in population databases (rs377767360, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg445*) 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). |
| Gene |
RCV000493396 | SCV000582779 | pathogenic | not provided | 2018-04-10 | criteria provided, single submitter | clinical testing | This variant is denoted SMAD4 c.1333C>T at the cDNA level and p.Arg445Ter (R445X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with juvenile polyposis syndrome (Woodford-Richens 2000, Handra-Luca 2005, Andrabi 2011) and is considered pathogenic. |
| Myriad Genetics, |
RCV000023059 | SCV004931948 | pathogenic | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 2024-02-09 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
| OMIM | RCV000023059 | SCV000044350 | pathogenic | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 2011-05-01 | no assertion criteria provided | literature only | |
| Institute of Medical Sciences, |
RCV001374448 | SCV001571412 | pathogenic | Gallbladder cancer | 2020-10-30 | no assertion criteria provided | research |