ClinVar Miner

Submissions for variant NM_005585.5(SMAD6):c.1184A>G (p.Lys395Arg)

gnomAD frequency: 0.00065  dbSNP: rs149949971
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000546579 SCV000650577 uncertain significance Aortic valve disease 2 2023-12-25 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 395 of the SMAD6 protein (p.Lys395Arg). This variant is present in population databases (rs149949971, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 471746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SMAD6 function (PMID: 32499606). 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.

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