ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1002G>T (p.Gln334His) (rs773598775)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481014 SCV000566641 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.1002G>T at the cDNA level, p.Gln334His (Q334H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Gln334His was not observed in large population cohorts (Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. SMAD4 Gln334His is located in the MH2 domain (UniProt). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether SMAD4 Gln334His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000701948 SCV000830774 uncertain significance Juvenile polyposis syndrome 2018-05-06 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 334 of the SMAD4 protein (p.Gln334His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 419077). 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 C15"). 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.

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