Submissions for variant NM_005585.5(SMAD6):c.531C>G (p.Tyr177Ter)

dbSNP: rs760571406

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797840	SCV000937424	uncertain significance	Aortic valve disease 2	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr177*) 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 variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 644007). 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.
Institute of Human Genetics, University of Goettingen	RCV000797840	SCV001468300	likely pathogenic	Aortic valve disease 2	2020-12-18	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000797840	SCV001572972	likely pathogenic	Aortic valve disease 2	2019-10-10	criteria provided, single submitter	clinical testing
GeneDx	RCV003128725	SCV003806074	likely pathogenic	not provided	2022-11-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
3billion, Medical Genetics	RCV000797840	SCV003841777	pathogenic	Aortic valve disease 2	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with SMAD6 related disorder (ClinVar ID: VCV000644007). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.