ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.527A>T (p.Glu176Val)

gnomAD frequency: 0.00001  dbSNP: rs756586319
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen RCV000654370 SCV005043105 uncertain significance DICER1-related tumor predisposition 2024-02-27 reviewed by expert panel curation The NM_177438.2:c.527A>T variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 176 (p.Glu176Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179702 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.835) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 02/27/2024)
Labcorp Genetics (formerly Invitae), Labcorp RCV000654370 SCV000776263 uncertain significance DICER1-related tumor predisposition 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 176 of the DICER1 protein (p.Glu176Val). This variant is present in population databases (rs756586319, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 543562). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function with a positive predictive value of 80%. 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.
Sema4, Sema4 RCV002255496 SCV002533056 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-17 criteria provided, single submitter curation
Ambry Genetics RCV002255496 SCV002644222 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-17 criteria provided, single submitter clinical testing The p.E176V variant (also known as c.527A>T), located in coding exon 4 of the DICER1 gene, results from an A to T substitution at nucleotide position 527. The glutamic acid at codon 176 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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