Submissions for variant NM_005359.6(SMAD4):c.682A>G (p.Ile228Val)

gnomAD frequency: 0.00001  dbSNP: rs1280682459

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759349	SCV000888629	uncertain significance	not provided	2018-02-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002386320	SCV001187939	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The p.I228V variant (also known as c.682A>G), located in coding exon 5 of the SMAD4 gene, results from an A to G substitution at nucleotide position 682. The isoleucine at codon 228 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.
Invitae	RCV001066745	SCV001231763	uncertain significance	Juvenile polyposis syndrome	2023-12-27	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 228 of the SMAD4 protein (p.Ile228Val). 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: 619726). 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.
GeneDx	RCV000759349	SCV002571600	uncertain significance	not provided	2022-09-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235019, 18823382, 22992590)
Baylor Genetics	RCV003472281	SCV004202591	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-07-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003584738	SCV004362345	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 228 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.