Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002232881 | SCV000816442 | uncertain significance | Juvenile polyposis syndrome | 2022-11-08 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. ClinVar contains an entry for this variant (Variation ID: 568457). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 531 of the SMAD4 protein (p.Arg531Trp). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001174759 | SCV001338076 | uncertain significance | not specified | 2020-01-14 | criteria provided, single submitter | clinical testing | Variant summary: SMAD4 c.1591C>T (p.Arg531Trp) results in a non-conservative amino acid change located in the SMAD Domain, Dwarfin-type (IPR00132) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251436 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1591C>T in individuals affected with Juvenile Polyposis Syndrome, Hereditary hemorrhagic telangiectasia, or Myhre syndrome in a germline/inherited context and no experimental evidence demonstrating its impact on protein function have been reported. The variant has however been observed in various sequencing studies of tumor samples obtained from the large intestine and pancreas as reported in somatic databases such as COSMIC. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV002397382 | SCV002709703 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2020-09-29 | criteria provided, single submitter | clinical testing | The p.R531W variant (also known as c.1591C>T), located in coding exon 11 of the SMAD4 gene, results from a C to T substitution at nucleotide position 1591. The arginine at codon 531 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |