ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.829A>G (p.Thr277Ala) (rs1555685960)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588293 SCV000698581 uncertain significance not provided 2016-12-29 criteria provided, single submitter clinical testing Variant summary: Variant summary: The SMAD4 c.829A>G (p.Thr277Ala) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121412 control chromosomes and has not been reported in any patients. Multiple functional studies have shown that Thr277 was located in the linker domain and phosphorylated by ERK and GSK3 (Roelen_2003, Demagny_2014). T277A causes loss of phosphorylation and decrease of the TGF-beta/SMAD4 pathway activity (Roelen_2003). All genes associated with a phenotype of HHT (Hereditary Hemorrahagic Telangectasia), which includes SMAD4, are known to be part of the TGF-beta signaling pathway, while SMAD4 also acts as a tumor suppressor in context of the JPC (Juvenile polyposis coli) phenotype. Mutations in several other genes within this pathway, are also known to cause familial thoracic aneurisms and aortic dissections. Taken together, this variant is classified as a variant of uncertain clinical significance (VUS) unless additional clinical and functional information to unequivocally establish its outcome are obtained.

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