Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_177438.2(DICER1):c.5465A>T (p.Asp1822Val)

CA10586400

254350 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 47c2c6a7-8144-418e-b4d0-69c01b152e08
Approved on: 2022-05-18
Published on: 2022-07-08

HGVS expressions

NM_177438.2:c.5465A>T
NM_177438.2(DICER1):c.5465A>T (p.Asp1822Val)
NC_000014.9:g.95091265T>A
CM000676.2:g.95091265T>A
NC_000014.8:g.95557602T>A
CM000676.1:g.95557602T>A
NC_000014.7:g.94627355T>A
NG_016311.1:g.71158A>T
ENST00000529720.2:c.5465A>T
ENST00000531162.7:c.5465A>T
ENST00000674628.2:c.5465A>T
ENST00000675540.2:c.*2115A>T
ENST00000696733.1:c.*87A>T
ENST00000696734.1:c.*120A>T
ENST00000696735.1:n.2452A>T
ENST00000696736.1:c.5465A>T
ENST00000696920.1:n.5728A>T
ENST00000696921.1:n.6571A>T
ENST00000696922.1:n.8396A>T
ENST00000696923.1:c.*120A>T
ENST00000696924.1:c.*87A>T
ENST00000696925.1:n.8396A>T
ENST00000343455.8:c.5465A>T
ENST00000393063.6:c.5465A>T
ENST00000526495.6:c.5465A>T
ENST00000556045.6:c.*182A>T
ENST00000675540.1:c.3210A>T
ENST00000675995.1:c.*3781A>T
ENST00000343455.7:c.5465A>T
ENST00000393063.5:c.5465A>T
ENST00000526495.5:c.5465A>T
ENST00000527414.5:c.5465A>T
ENST00000527416.2:n.58A>T
ENST00000527554.2:n.158A>T
ENST00000541352.5:c.5365-156A>T
ENST00000556045.5:c.2159A>T
NM_001195573.1:c.5365-156A>T
NM_001271282.2:c.5465A>T
NM_001291628.1:c.5465A>T
NM_030621.4:c.5465A>T
NM_001271282.3:c.5465A>T
NM_001291628.2:c.5465A>T
NM_177438.3:c.5465A>T
NM_001395677.1:c.5465A>T
NM_001395678.1:c.5465A>T
NM_001395679.1:c.5465A>T
NM_001395680.1:c.5465A>T
NM_001395682.1:c.5465A>T
NM_001395683.1:c.5465A>T
NM_001395684.1:c.5465A>T
NM_001395685.1:c.5465A>T
NM_001395686.1:c.5183A>T
NM_001395687.1:c.5060A>T
NM_001395688.1:c.5060A>T
NM_001395689.1:c.5060A>T
NM_001395690.1:c.5060A>T
NM_001395691.1:c.4898A>T
NM_001395697.1:c.3782A>T
NR_172715.1:n.5883A>T
NR_172716.1:n.6067A>T
NR_172717.1:n.5977A>T
NR_172718.1:n.5900A>T
NR_172719.1:n.5733A>T
NR_172720.1:n.5936A>T
More

Likely Pathogenic

Met criteria codes 5
PS3_Supporting PS4_Moderate PM2_Supporting PM1_Supporting PP3
Not Met criteria codes 8
BS1 BS4 BS3 PS1 PS2 BA1 PVS1 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.2:c.5465A>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1822 (p.Asp1822Val). This variant received a total of 3 phenotype points across 3 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 21266384) (PS4_Moderate). This variant is absent from gnomAD v2.1.1 and v.3.1.1 (PM2_Supporting). In vitro cleavage assay in HEK293 cells showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University)(PS3_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592) (PM1_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, 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_Moderate, PM1_Supporting, PM2_supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1; 02/11/2022)
Met criteria codes
PS3_Supporting
Wu et al. 2018. PhD Thesis. "DICER1 syndrome: assays, associations and models" - Evaluated via in vitro cleavage assay per table 2.1; table 3.1; table 3.2 and 6.3 cleavage products = “Delayed to no 5p and 3p”; AKA Mutation 33; No reported paired somatic mutations identified yet.
PS4_Moderate
3 points; Reported in 2 individuals with PPB (Brenneman et al. 2015. PMID: 26925222; 2 points); Reported in a proband with PPB (4y) and their parent with thyroid cysts (30y) (Family 11, Slade et al. 2011. PMID: 21266384; 1 point).
PM2_Supporting
Absent in gnomAD. Coverage is >20X.
PM1_Supporting
Missense variant in Rnase IIIb domain (p.Y1682 – p.S1846)
PP3
REVEL=0.954; Splice AI Donor Gain Δ0.56 and Donor Loss Δ0.26; MaxEntScan cryptic donor GT site 64 (63?)nt upstream of 3’ ss, cryptic site 7.07 (up from 0) and native site 5.64 (unchanged)
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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