Submissions for variant NM_005359.6(SMAD4):c.220A>G (p.Ile74Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002425832	SCV002728286	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.I74V variant (also known as c.220A>G), located in coding exon 1 of the SMAD4 gene, results from an A to G substitution at nucleotide position 220. The isoleucine at codon 74 is replaced by valine, an amino acid with highly 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.
All of Us Research Program, National Institutes of Health	RCV004007407	SCV004824168	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 74 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 1/251074 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.