ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.754C>T (p.Gln252Ter) (rs1566999458)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760821 SCV000890716 likely pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing The Q252X likely pathogenic variant in the SMAD3 gene has not been reported as a pathogenic or benign to our knowledge. This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the SMAD3 gene have been reported in Human Gene Mutation Database in association with SMAD3-related disorders (Stenson et al., 2014). Furthermore, the Q252X variant is not observed in large population cohorts (Lek et al., 2016). In summary, Q252X in the SMAD3 gene is interpreted as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193562 SCV001362472 likely pathogenic Familial aortopathy 2019-09-16 criteria provided, single submitter clinical testing Variant summary: SMAD3 c.754C>T (p.Gln252X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251198 control chromosomes (gnomAD). To our knowledge, no occurrence of c.754C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001381115 SCV001579367 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-08-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln252*) in the SMAD3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 620443). Loss-of-function variants in SMAD3 are known to be pathogenic (PMID: 21778426, 24804794). For these reasons, this variant has been classified as Pathogenic.

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