ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1495T>C (p.Cys499Arg) (rs1060500738)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489838 SCV000577781 likely pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.1495T>C at the cDNA level, p.Cys499Arg (C499R) at the protein level, and results in the change of a Cysteine to an Arginine (TGC>CGC). While this variant has been reported as a somatic variant, it has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. SMAD4 Cys499Arg was not observed in large population cohorts (Lek 2016). This variant is located in the MH2 domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Additionally, the phenotypes reported in individuals harboring SMAD4 Cys499Arg at this laboratory have been consistent with Juvenile Polyposis syndrome (JPS). Based on currently available evidence, we consider SMAD4 Cys499Arg to be a likely pathogenic variant.
Invitae RCV000460831 SCV000543748 uncertain significance Juvenile polyposis syndrome 2016-06-10 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 499 of the SMAD4 protein (p.Cys499Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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