ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.907C>G (p.Pro303Ala)

dbSNP: rs1568206575
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773779 SCV000907479 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-17 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 303 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-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.
Ambry Genetics RCV002386341 SCV001180077 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2023-02-13 criteria provided, single submitter clinical testing The p.P303A variant (also known as c.907C>G), located in coding exon 7 of the SMAD4 gene, results from a C to G substitution at nucleotide position 907. The proline at codon 303 is replaced by alanine, 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.
Invitae RCV001208046 SCV001379418 uncertain significance Juvenile polyposis syndrome 2019-10-20 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 629090). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 303 of the SMAD4 protein (p.Pro303Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine.

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