ClinVar Miner

Submissions for variant NM_005585.5(SMAD6):c.598G>A (p.Gly200Ser)

gnomAD frequency: 0.00001  dbSNP: rs1039327779
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001051777 SCV001215954 uncertain significance Aortic valve disease 2 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 200 of the SMAD6 protein (p.Gly200Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 848092). 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%. 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.
Ambry Genetics RCV002355035 SCV002658757 uncertain significance Inborn genetic diseases 2024-03-10 criteria provided, single submitter clinical testing The p.G200S variant (also known as c.598G>A), located in coding exon 1 of the SMAD6 gene, results from a G to A substitution at nucleotide position 598. The glycine at codon 200 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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