ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.626C>T (p.Thr209Ile)

dbSNP: rs1909801469
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001201619 SCV001372697 uncertain significance Juvenile polyposis syndrome 2023-07-03 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: 933412). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 209 of the SMAD4 protein (p.Thr209Ile). 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.
Ambry Genetics RCV002365902 SCV002660023 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2020-12-17 criteria provided, single submitter clinical testing The p.T209I variant (also known as c.626C>T), located in coding exon 4 of the SMAD4 gene, results from a C to T substitution at nucleotide position 626. The threonine at codon 209 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well 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.

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