ClinVar Miner

Submissions for variant NM_177438.2(DICER1):c.4189T>C (p.Trp1397Arg) (rs762677393)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575344 SCV000661892 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
GeneDx RCV000486377 SCV000571881 uncertain significance not provided 2016-10-05 criteria provided, single submitter clinical testing This variant is denoted DICER1 c.4189T>C at the cDNA level, p.Trp1397Arg (W1397R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. DICER1 Trp1397Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. DICER1 Trp1397Arg occurs at a position that is conserved in mammals and is located in the RNase III 1 domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether DICER1 Trp1397Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227035 SCV000291676 uncertain significance DICER1-related pleuropulmonary blastoma cancer predisposition syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 1397 of the DICER1 protein (p.Trp1397Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs762677393, ExAC 0.002%). This variant has not been reported in the literature in individuals with DICER1-related disease. ClinVar contains an entry for this variant (Variation ID: 242101). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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