Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000635433 | SCV000756846 | uncertain significance | Juvenile polyposis syndrome | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 233 of the SMAD4 protein (p.His233Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 529909). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function with a negative predictive value of 95%. 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. |
ARUP Laboratories, |
RCV000756670 | SCV000884553 | uncertain significance | not provided | 2018-04-16 | criteria provided, single submitter | clinical testing | The SMAD4 c.698A>G; p.His233Arg variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at codon 233 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.His233Arg variant is uncertain at this time. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780717 | SCV000918225 | uncertain significance | not specified | 2018-03-30 | criteria provided, single submitter | clinical testing | Variant summary: SMAD4 c.698A>G (p.His233Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 121270 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.698A>G in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Ambry Genetics | RCV002360541 | SCV002665333 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2022-12-15 | criteria provided, single submitter | clinical testing | The p.H233R variant (also known as c.698A>G), located in coding exon 5 of the SMAD4 gene, results from an A to G substitution at nucleotide position 698. The histidine at codon 233 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |