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Variant: NM_030621.4(DICER1):c.5441C>T (p.Ser1814Leu)

CA16614268

412119 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8e7cfae4-6aa0-43c2-bd8e-ac97698ead21
Approved on: 2022-05-18
Published on: 2022-07-08

HGVS expressions

NM_030621.4:c.5441C>T
NM_030621.4(DICER1):c.5441C>T (p.Ser1814Leu)
NC_000014.9:g.95091289G>A
CM000676.2:g.95091289G>A
NC_000014.8:g.95557626G>A
CM000676.1:g.95557626G>A
NC_000014.7:g.94627379G>A
NG_016311.1:g.71134C>T
ENST00000343455.8:c.5441C>T
ENST00000393063.6:c.5441C>T
ENST00000526495.6:c.5441C>T
ENST00000556045.6:c.*158C>T
ENST00000675540.1:n.3186C>T
ENST00000675995.1:c.*3757C>T
ENST00000343455.7:c.5441C>T
ENST00000393063.5:c.5441C>T
ENST00000526495.5:c.5441C>T
ENST00000527414.5:c.5441C>T
ENST00000527416.2:n.34C>T
ENST00000527554.2:n.134C>T
ENST00000541352.5:c.5365-180C>T
ENST00000556045.5:c.2135C>T
NM_001195573.1:c.5365-180C>T
NM_001271282.2:c.5441C>T
NM_001291628.1:c.5441C>T
NM_177438.2:c.5441C>T
NM_001271282.3:c.5441C>T
NM_001291628.2:c.5441C>T
NM_177438.3:c.5441C>T
NM_001395677.1:c.5441C>T
NM_001395678.1:c.5441C>T
NM_001395679.1:c.5441C>T
NM_001395680.1:c.5441C>T
NM_001395682.1:c.5441C>T
NM_001395683.1:c.5441C>T
NM_001395684.1:c.5441C>T
NM_001395685.1:c.5441C>T
NM_001395686.1:c.5159C>T
NM_001395687.1:c.5036C>T
NM_001395688.1:c.5036C>T
NM_001395689.1:c.5036C>T
NM_001395690.1:c.5036C>T
NM_001395691.1:c.4874C>T
NM_001395697.1:c.3758C>T
NR_172715.1:n.5859C>T
NR_172716.1:n.6043C>T
NR_172717.1:n.5953C>T
NR_172718.1:n.5876C>T
NR_172719.1:n.5709C>T
NR_172720.1:n.5912C>T
NM_177438.3(DICER1):c.5441C>T (p.Ser1814Leu)

Pathogenic

Met criteria codes 7
PP4 PP3 PS4 PM1_Supporting PM2_Supporting PP1_Strong PS3_Supporting
Not Met criteria codes 9
PM5 PM6 PS2 PS1 BA1 BP4 BS4 BS3 BS1

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
NM_177438.2(DICER1):c.5441C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by leucine at amino acid 1814 (p.Ser1814Leu). This variant received a total of 4.5 phenotype points across 5 unrelated probands/families meeting DICER1 VCEP phenotype specificity scoring criteria of >4 points (PS4; PMIDs: 26545620, 26555935, ClinVar GTRs: 239772, 500031, 500086). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 syndrome (PP4, PMIDs: 26555935). The variant has been reported to segregate with disease in multiple affected family members with 7 meioses from 3 families (PP1_Strong; PMIDs: 26555935, ClinVar SCVs: SCV000553579.6). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer)(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 (PS3_Supporting; PMIDs: 26545620). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functional as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.889, 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 Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4, PP4, PP1_Strong, PM2_Supporting, PS3_Supporting, PM1_Supporting, PP3 (Bayesian Points: 13; VCEP specifications version 1; 02/11/2022).
Met criteria codes
PP4
Rutter et al 2016 - Proband somatic p.Asp1709Gly, Sister1 somatic p.Gly1809Arg, Brother somatic p.Asp1709Gly and p.Asp1810His. Sister 2 did not have somatic variants identified. Wu et al. 2016 - Proband had somatic second hit c.5125G>A;p.D1709N in SLCT and c.5428G>T p.D1810Y in MNG
PP3
REVEL score = 0.889 >0.75; no splice impact predicted
PS4
Total = 4.5points
PM1_Supporting
Missense variants affecting in the RNAse IIIb domain (p.Y1682-p.S1846)
PM2_Supporting
Absent in gnomAD
PP1_Strong
From Rutter et al 2016 (5 meiosis across 1 family); NCI (1 meiosis, father to son both w/ PPB); Invitae (1 meiosis mother/daughter w/ SLCT) Total of 7 meioses across 3 families
PS3_Supporting
Wu et al 2016 - In vitro cleavage assay for S1814L – reduced 5p and 3p miRNA generation and produces some 5p miRNA+loop (5p+loop), as compared to a normal DICER1 protein. Defect in miRNA processing.
Not Met criteria codes
PM5
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
PS2
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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