Submissions for variant NM_005585.5(SMAD6):c.1360G>C (p.Ala454Pro)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002599215	SCV003496561	uncertain significance	Aortic valve disease 2	2023-06-11	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 2179628). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 454 of the SMAD6 protein (p.Ala454Pro). 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.
PreventionGenetics, part of Exact Sciences	RCV004744595	SCV005361874	uncertain significance	SMAD6-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The SMAD6 c.1360G>C variant is predicted to result in the amino acid substitution p.Ala454Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.