Submissions for variant NM_005359.6(SMAD4):c.1490G>A (p.Arg497His)

dbSNP: rs1910519516

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001232926	SCV001405499	uncertain significance	Juvenile polyposis syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 497 of the SMAD4 protein (p.Arg497His). 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: 959550). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 14647410). 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.
Ambry Genetics	RCV002393579	SCV002700056	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2024-06-27	criteria provided, single submitter	clinical testing	The p.R497H variant (also known as c.1490G>A), located in coding exon 11 of the SMAD4 gene, results from a G to A substitution at nucleotide position 1490. The arginine at codon 497 is replaced by histidine, an amino acid with highly similar properties. In one functional study, this variant reportedly demonstrated reduced ability to transactivate a TGF-β responsive reporter gene, reduced binding to DNA as well as SMAD2, and enhanced ability to inhibit TGF-β signaling compared to the wild type SMAD4 protein (Kuang C et al. Oncogene, 2004 Feb;23:1021-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear for juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia and its clinical significance for Myhre syndrome is uncertain.
GeneDx	RCV004797913	SCV005420199	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate partial inhibition of SMAD2 interaction and significantly attenuated DNA binding activity (PMID: 14647410); This variant is associated with the following publications: (PMID: 17873119, 18823382, 15235019, 14647410)
All of Us Research Program, National Institutes of Health	RCV004803587	SCV005425383	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 497 of the SMAD4 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has demonstrated this variant negatively impacts transcriptional activity, as well as DNA and SMAD2 binding, compared to wild type protein (PMID: 14647410). 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.