ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.16A>G (p.Ile6Val)

dbSNP: rs1376500870
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002311914 SCV000672000 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2023-02-03 criteria provided, single submitter clinical testing The p.I6V variant (also known as c.16A>G), located in coding exon 1 of the SMAD4 gene, results from an A to G substitution at nucleotide position 16. The isoleucine at codon 6 is replaced by valine, an amino acid with highly similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health RCV000569854 SCV000686530 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
Invitae RCV001243344 SCV001416497 uncertain significance Juvenile polyposis syndrome 2023-05-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the SMAD4 protein (p.Ile6Val). 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: 484798). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%).
GeneDx RCV001764673 SCV002000468 uncertain significance not provided 2021-04-14 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 484798; Landrum et al., 2016)

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