ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.556C>G (p.Pro186Ala)

dbSNP: rs1555685648
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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 RCV002311933 SCV000672029 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2016-12-14 criteria provided, single submitter clinical testing The p.P186A variant (also known as c.556C>G), located in coding exon 4 of the SMAD4 gene, results from a C to G substitution at nucleotide position 556. The proline at codon 186 is replaced by alanine, 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.
Invitae RCV002232142 SCV000964219 uncertain significance Juvenile polyposis syndrome 2021-10-27 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function. ClinVar contains an entry for this variant (Variation ID: 484817). 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 proline, a(n) neutral and non-polar amino acid, with alanine, a(n) neutral and non-polar amino acid, at codon 186 of the SMAD4 protein (p.Pro186Ala).

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