ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.997G>A (p.Val333Ile)

dbSNP: rs1274926456
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000800540 SCV000940263 uncertain significance Juvenile polyposis syndrome 2025-01-07 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 333 of the SMAD4 protein (p.Val333Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 646287). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. 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.
Ambry Genetics RCV002442655 SCV001181374 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2024-01-05 criteria provided, single submitter clinical testing The p.V333I variant (also known as c.997G>A), located in coding exon 8 of the SMAD4 gene, results from a G to A substitution at nucleotide position 997. The valine at codon 333 is replaced by isoleucine, 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 RCV004803226 SCV005424215 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2024-08-06 criteria provided, single submitter clinical testing
GeneDx RCV005241405 SCV005888708 uncertain significance not provided 2024-09-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17873119, 18823382, 15235019)

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