ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.884C>T (p.Pro295Leu)

gnomAD frequency: 0.00002  dbSNP: rs370176106
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234236 SCV000288882 uncertain significance Juvenile polyposis syndrome 2022-10-31 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 295 of the SMAD4 protein (p.Pro295Leu). This variant is present in population databases (rs370176106, gnomAD 0.03%). 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: 240155). 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. 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.
GeneDx RCV000479945 SCV000567362 uncertain significance not provided 2023-02-27 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30267214, 10636916)
Ambry Genetics RCV002311353 SCV000671984 likely benign Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2022-11-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000576051 SCV000686563 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-08 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 295 of the SMAD4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 5/251480 chromosomes 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.
Baylor Genetics RCV003475829 SCV004202579 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2023-09-12 criteria provided, single submitter clinical testing

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