ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.679A>G (p.Ser227Gly)

gnomAD frequency: 0.00001  dbSNP: rs1443767329
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000777492 SCV000913354 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-26 criteria provided, single submitter clinical testing This missense variant replaces serine with glycine at codon 227 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001221876 SCV001393945 uncertain significance Juvenile polyposis syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 227 of the SMAD4 protein (p.Ser227Gly). 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: 631311). 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.
Ambry Genetics RCV002360895 SCV002663787 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2022-01-26 criteria provided, single submitter clinical testing The p.S227G variant (also known as c.679A>G), located in coding exon 5 of the SMAD4 gene, results from an A to G substitution at nucleotide position 679. The serine at codon 227 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. 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.

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