ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1499T>C (p.Ile500Thr) (rs281875321)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000023060 SCV000693905 pathogenic Myhre syndrome 2017-06-26 criteria provided, single submitter research Previously reported pathogenic variant, de novo in this case with maternity and paternity confirmed (PS2).
GeneDx RCV000059734 SCV000617742 pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing The I500T variant in the SMAD4 gene has been reported previously in multiple unrelated individuals with Myhre syndrome (Le et al., 2011; Caputo et al., 2012; Lindor et al., 2012; Michot et al., 2014; Garavelli et al., 2016; Lin et al., 2016). One in vitro functional study concluded this variant results in increased SMAD4 protein level, which results in increased phosphorylation of other SMAD proteins in the nucleus, however additional studies are needed to validate the functional effect of this variant in vivo (Le et al., 2011). The I500T variant is not observed in large population cohorts (Lek et al., 2016). The I500T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs in the MH2 domain at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in the same residue (I500V, I500M) have been reported in association with Myhre syndrome, supporting the functional importance of this region of the protein (Le et al., 2011). We interpret I500T as a pathogenic variant.
GeneReviews RCV000023060 SCV000564087 pathogenic Myhre syndrome 2017-01-31 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000059734 SCV000692040 pathogenic not provided no assertion criteria provided clinical testing
OMIM RCV000023060 SCV000044351 pathogenic Myhre syndrome 2012-06-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000059734 SCV000091304 not provided not provided no assertion provided not provided
Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale) RCV000023060 SCV000106024 pathogenic Myhre syndrome no assertion criteria provided not provided Converted during submission to Pathogenic.

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