ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.717G>C (p.Gln239His)

dbSNP: rs1599189519
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002409347 SCV001188442 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2024-11-16 criteria provided, single submitter clinical testing The p.Q239H variant (also known as c.717G>C), located in coding exon 5 of the SMAD4 gene, results from a G to C substitution at nucleotide position 717. The glutamine at codon 239 is replaced by histidine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001237884 SCV001410667 uncertain significance Juvenile polyposis syndrome 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 239 of the SMAD4 protein (p.Gln239His). 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: 826889). 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 not expected to disrupt SMAD4 protein function with a negative predictive value of 95%. 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 RCV001026123 SCV002538343 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-26 criteria provided, single submitter curation

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