Submissions for variant NM_005359.6(SMAD4):c.932A>G (p.Gln311Arg)

gnomAD frequency: 0.00001  dbSNP: rs1381679797

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001345423	SCV001539536	uncertain significance	Juvenile polyposis syndrome	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 311 of the SMAD4 protein (p.Gln311Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 1041597). 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) has been performed at Invitae 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. 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.
Sema4, Sema4	RCV002258212	SCV002538358	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	curation
Ambry Genetics	RCV002377466	SCV002686744	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2024-07-02	criteria provided, single submitter	clinical testing	The p.Q311R variant (also known as c.932A>G), located in coding exon 7 of the SMAD4 gene, results from an A to G substitution at nucleotide position 932. The glutamine at codon 311 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
All of Us Research Program, National Institutes of Health	RCV004005197	SCV004828121	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 311 of the SMAD4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 1/31398 chromosomes 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.
Baylor Genetics	RCV004005197	SCV005052703	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-12-28	criteria provided, single submitter	clinical testing
GeneDx	RCV004770081	SCV005377905	uncertain significance	not provided	2023-10-25	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: 10636916)