Submissions for variant NM_005585.5(SMAD6):c.1055_1056insAT (p.Ala353fs)

dbSNP: rs2140681355

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001581206	SCV001811851	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing	Identified in a family with craniosynostosis. Affected members of the family carried a common risk allele in BMP2 (Timberlake et al., 2016); Frameshift variant resulting in protein extension where the last 144 amino acids are lost and replaced with 186 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27606499)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003533010	SCV004297625	uncertain significance	Aortic valve disease 2	2022-11-02	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 and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1210484). This frameshift has been observed in individual(s) with craniosynostosis (PMID: 27606499). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the SMAD6 gene (p.Ala353Trpfs*187). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the SMAD6 protein and extend the protein by 42 additional amino acid residues.