ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.394C>T (p.His132Tyr)

dbSNP: rs1060500743
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456145 SCV000543756 uncertain significance Juvenile polyposis syndrome 2022-09-05 criteria provided, single submitter clinical testing 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. 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 SMAD4 protein function. ClinVar contains an entry for this variant (Variation ID: 405501). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 132 of the SMAD4 protein (p.His132Tyr).
Ambry Genetics RCV002356652 SCV002621026 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2016-08-01 criteria provided, single submitter clinical testing The p.H132Y variant (also known as c.394C>T), located in coding exon 2 of the SMAD4 gene, results from a C to T substitution at nucleotide position 394. The histidine at codon 132 is replaced by tyrosine, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with SMAD4-related disease (Ambry internal data). Based on internal structural analysis, H132Y disrupts a conserved zinc-binding site which is important to structural stability and DNA-binding (Ambry internal data; Chai J et al. J Biol Chem, 2003 May;278:20327-31; BabuRajendran N et al. Nucleic Acids Res, 2010 Jun;38:3477-88; Martin-Malpartida P et al. Nat Commun, 2017 12;8:2070). 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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