ClinVar Miner

Submissions for variant NM_005585.5(SMAD6):c.1244C>T (p.Pro415Leu)

dbSNP: rs387907284
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000030754 SCV002297697 uncertain significance Aortic valve disease 2 2021-08-23 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. Experimental studies have shown that this missense change affects SMAD6 function (PMID: 22275001). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 37112). This missense change has been observed in individual(s) with aortic stenosis with bicuspid aortic valve (PMID: 22275001, 30848080). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 415 of the SMAD6 protein (p.Pro415Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
GeneDx RCV003329236 SCV004036357 uncertain significance not provided 2023-03-24 criteria provided, single submitter clinical testing Identified in an infant with bicuspid aortic valve and moderate aortic stenosis in the published literature, however, familial segregation information was not included (Tan et al., 2012); Published functional studies suggest a mild decrease in protein signaling compared to wild type protein (Tan et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22275001)
OMIM RCV000030754 SCV000053415 pathogenic Aortic valve disease 2 2012-04-01 no assertion criteria provided literature only

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