Submissions for variant NM_005585.5(SMAD6):c.508C>T (p.Gln170Ter)

dbSNP: rs1235097131

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358994	SCV001554854	uncertain significance	Aortic valve disease 2	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln170*) in the SMAD6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SMAD6 cause disease. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with radioulnar synostosis (PMID: 34953066). ClinVar contains an entry for this variant (Variation ID: 1051015). 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	RCV002293529	SCV002586905	pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	Reported apparently de novo in a proband with bilateral radioulnar synostosis, but no other clinical information was provided (PMID: 34953066); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34953066)
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001799763	SCV001739407	pathogenic	Radioulnar synostosis	2020-06-20	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004743426	SCV005355633	uncertain significance	SMAD6-related disorder	2024-03-04	no assertion criteria provided	clinical testing	The SMAD6 c.508C>T variant is predicted to result in premature protein termination (p.Gln170*). This variant was reported as a de novo variant in an individual with radioulnar synostosis (Shen et al 2022. PubMed ID: 34953066). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.