ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.503G>A (p.Gly168Glu)

dbSNP: rs1555685631
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002311949 SCV000672047 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2017-09-12 criteria provided, single submitter clinical testing The p.G168E variant (also known as c.503G>A), located in coding exon 4 of the SMAD4 gene, results from a G to A substitution at nucleotide position 503. The glycine at codon 168 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003767205 SCV004681779 uncertain significance Juvenile polyposis syndrome 2023-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 168 of the SMAD4 protein (p.Gly168Glu). 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: 484833). 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.

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