ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.1250C>T (p.Pro417Leu)

dbSNP: rs1963334413
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001296811 SCV001485785 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-09-06 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 417 of the SMAD3 protein (p.Pro417Leu). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt SMAD3 protein function. ClinVar contains an entry for this variant (Variation ID: 1000654). This missense change has been observed in individual(s) with thoracic aortic aneurysm and/or dissection (Invitae). It has also been observed to segregate with disease in related individuals.
Ambry Genetics RCV001296811 SCV002674722 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-01-04 criteria provided, single submitter clinical testing The p.P417L variant (also known as c.1250C>T), located in coding exon 9 of the SMAD3 gene, results from a C to T substitution at nucleotide position 1250. The proline at codon 417 is replaced by leucine, an amino acid with similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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.

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