Submissions for variant NM_005902.4(SMAD3):c.1186A>G (p.Ile396Val)

gnomAD frequency: 0.00003  dbSNP: rs1317532064

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691553	SCV000819339	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-09-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000691553	SCV001357951	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 396 of the SMAD3 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 SMAD3-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.
GeneDx	RCV001592880	SCV001816891	uncertain significance	not provided	2020-08-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 570649; Landrum et al., 2016)
AiLife Diagnostics, AiLife Diagnostics	RCV001592880	SCV002503179	uncertain significance	not provided	2021-12-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279488	SCV002566092	uncertain significance	Ehlers-Danlos syndrome	2020-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307592	SCV002600520	uncertain significance	not specified	2023-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000691553	SCV002635113	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-12	criteria provided, single submitter	clinical testing	The p.I396V variant (also known as c.1186A>G), located in coding exon 9 of the SMAD3 gene, results from an A to G substitution at nucleotide position 1186. The isoleucine at codon 396 is replaced by valine, an amino acid with highly similar properties. 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.
All of Us Research Program, National Institutes of Health	RCV003999560	SCV004815423	uncertain significance	Aneurysm-osteoarthritis syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 396 of the SMAD3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular 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.