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
Labcorp Genetics (formerly Invitae), Labcorp RCV000030754 SCV002297697 uncertain significance Aortic valve disease 2 2024-12-30 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 415 of the SMAD6 protein (p.Pro415Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aortic stenosis with bicuspid aortic valve (PMID: 22275001, 30848080). ClinVar contains an entry for this variant (Variation ID: 37112). 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 SMAD6 protein function. Experimental studies have shown that this missense change affects SMAD6 function (PMID: 22275001). 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 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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