Submissions for variant NM_177438.3(DICER1):c.1509G>C (p.Glu503Asp)

dbSNP: rs1595414866

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV002008881	SCV003803733	likely pathogenic	DICER1-related tumor predisposition	2023-01-23	reviewed by expert panel	curation	NM_177438.2(DICER1):c.1509G>C variant in DICER1 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). This variant received a total of 1 phenotype point across 1 unrelated proband/family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab data: Invitae). The variant has been reported to segregate with disease in 1 affected family member, with 4 meioses from 1 family (PP1; Internal lab data: Invitae). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor: Invitae). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP1, PM2_Supporting, PS3, PP3 (Bayesian Points: 8; VCEP specifications version 1.1.0; 01/23/23).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002008881	SCV002276098	pathogenic	DICER1-related tumor predisposition	2022-05-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 9 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of DICER1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 503 of the DICER1 protein (p.Glu503Asp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.