ClinVar Miner

Submissions for variant NM_177438.2(DICER1):c.3118A>G (p.Ile1040Val) (rs1555370052)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497463 SCV000589975 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing The I1040V variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. This substitution occurs at a position that is conserved across species and is located within the PAZ domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, we consider I1040V to be a variant of uncertain significance.
Invitae RCV000685635 SCV000813121 uncertain significance DICER1-related pleuropulmonary blastoma cancer predisposition syndrome 2018-10-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1040 of the DICER1 protein (p.Ile1040Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DICER1-related disease. ClinVar contains an entry for this variant (Variation ID: 432263). 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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