Submissions for variant NM_005359.6(SMAD4):c.926C>T (p.Ala309Val)

dbSNP: rs1599191240

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002409336	SCV001180414	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	The p.A309V variant (also known as c.926C>T), located in coding exon 7 of the SMAD4 gene, results from a C to T substitution at nucleotide position 926. The alanine at codon 309 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800928	SCV002046287	uncertain significance	not specified	2020-10-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549497	SCV003471817	uncertain significance	Juvenile polyposis syndrome	2024-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 309 of the SMAD4 protein (p.Ala309Val). 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: 823137). 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.
Baylor Genetics	RCV003473585	SCV004202568	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003473585	SCV005424214	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 309 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 been reported in an individual affected with Peutz-Jeghers syndrome (PMID: 37377590). 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.