ClinVar Genomic variation as it relates to human health
NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg)
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg)
Variation ID: 242032 Accession: VCV000242032.56
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q32.13 14: 95124448 (GRCh38) [ NCBI UCSC ] 14: 95590785 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 May 25, 2025 Aug 22, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_177438.3:c.1124C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_803187.1:p.Pro375Arg missense NM_001195573.1:c.1124C>G NP_001182502.1:p.Pro375Arg missense NM_001271282.3:c.1124C>G NP_001258211.1:p.Pro375Arg missense NM_001291628.2:c.1124C>G NP_001278557.1:p.Pro375Arg missense NM_030621.4:c.1124C>G NP_085124.2:p.Pro375Arg missense NC_000014.9:g.95124448G>C NC_000014.8:g.95590785G>C NG_016311.1:g.37975C>G LRG_492:g.37975C>G LRG_492t1:c.1124C>G LRG_492p1:p.Pro375Arg - Protein change
- P375R
- Other names
-
NM_177438.3(DICER1):c.1124C>G
p.Pro375Arg
- Canonical SPDI
- NC_000014.9:95124447:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00025
The Genome Aggregation Database (gnomAD) 0.00027
Trans-Omics for Precision Medicine (TOPMed) 0.00027
1000 Genomes Project 30x 0.00031
Exome Aggregation Consortium (ExAC) 0.00035
The Genome Aggregation Database (gnomAD), exomes 0.00035
The Genome Aggregation Database (gnomAD), exomes 0.00038
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
DICER1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7058 | 7097 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Benign (5) |
reviewed by expert panel
|
Aug 22, 2023 | RCV000231396.26 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 19, 2024 | RCV000570796.7 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2025 | RCV001201043.15 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 10, 2020 | RCV001292801.6 | |
Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 1, 2025 | RCV002469086.23 | |
DICER1-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Apr 20, 2022 | RCV003977693.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Benign
(Aug 22, 2023)
C
Contributing to aggregate classification
|
reviewed by expert panel
Method: curation
|
DICER1-related tumor predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004032135.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
The NM_177438.2:c.1124C>G variant in DICER1 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 375 (p.Pro375Arg). This variant has … (more)
The NM_177438.2:c.1124C>G variant in DICER1 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 375 (p.Pro375Arg). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors, PMIDs 29641532, 33630087). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004911 (58/118098 alleles) in the European (non-Finnish) population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met). The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2. (Bayesian Points: -8; VCEP specifications version 1.2.0; 08/22/23). (less)
|
|
Likely benign
(Oct 07, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
DICER1-related tumor predisposition
Affected status: no
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000891032.2
First in ClinVar: Mar 19, 2019 Last updated: Dec 17, 2020 |
Comment:
The DICER1 c.1124C>G (p.Pro375Arg) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95590785-G-C). This population frequency is higher than expected for … (more)
The DICER1 c.1124C>G (p.Pro375Arg) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95590785-G-C). This population frequency is higher than expected for DICER1-related cancer predisposition syndrome (BS1, PMID: 24761742). Although this variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533), but in silico tools are not in agreement about the effect of this variant on protein function. This variant has been reported in an individual with papillary thyroid carcinoma whose tumor harbored a somatic DICER1 p.D1810Y variant and loss of the allele that carried the germline p.P375R variant (BP5; PMID: 29474644). This suggests that this variant is not deleterious. To our knowledge, this variant has not been reported in individuals with a personal or family history suggestive of DICER1 Tumor Predisposition syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP5, PP2. (less)
|
|
Uncertain significance
(Apr 10, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Euthyroid goiter
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481455.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Benign
(Jul 01, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: curation
|
Not Specified
Affected status: yes
Allele origin:
germline
|
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Accession: SCV001372045.2
First in ClinVar: Jul 16, 2020 Last updated: Sep 08, 2021 |
Comment:
ACMG criteria met: PP5, BS1, BS2, BP1
Number of individuals with the variant: 1
|
|
Likely benign
(May 10, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532439.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
Uncertain significance
(Aug 26, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002765203.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with CNS sarcoma, thyroid, and other cancers, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with CNS sarcoma, thyroid, and other cancers, but also in unaffected controls (Slade 2011, Mandelker 2017, Pritchard 2018, Wasserman 2018, Kamihara 2020); This variant is associated with the following publications: (PMID: 21266384, 29474644, 28873162, 29641532, 28748527, 32291395) (less)
|
|
Uncertain significance
(Nov 03, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010938.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
Likely benign
(Aug 31, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774143.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
|
|
Likely benign
(Jan 27, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000661811.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Benign
(Dec 19, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Hereditary Cancer Group, L’Institut d'Investigació Biomèdica de Bellvitge
Accession: SCV005442421.1
First in ClinVar: Jan 04, 2025 Last updated: Jan 04, 2025 |
Comment:
BS1, BS2
|
|
Benign
(Feb 02, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
DICER1-related tumor predisposition
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000291603.12
First in ClinVar: Jul 01, 2016 Last updated: Feb 25, 2025 |
|
|
Benign
(Mar 04, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551564.7
First in ClinVar: Jul 27, 2022 Last updated: Mar 11, 2025 |
|
|
Uncertain significance
(Aug 28, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
DICER1-related tumor predisposition
Affected status: yes
Allele origin:
germline
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV005912861.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
|
|
Likely benign
(Jan 01, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004130334.14
First in ClinVar: Nov 20, 2023 Last updated: May 25, 2025 |
Comment:
DICER1: PP2, BS1
Number of individuals with the variant: 2
|
|
Benign
(Jan 12, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Pleuropulmonary blastoma
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000389766.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Uncertain significance
(May 09, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV003839422.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the DICER1 gene demonstrated a sequence change, c.1124C>G, in exon 8 that results in an amino acid change, p.Pro375Arg. This sequence … (more)
DNA sequence analysis of the DICER1 gene demonstrated a sequence change, c.1124C>G, in exon 8 that results in an amino acid change, p.Pro375Arg. This sequence change does not appear to have been previously described in individuals with DICER1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.050% in the European subpopulation (dbSNP rs148758903). The p.Pro375Arg change affects a highly conserved amino acid residue located in a domain of the DICER1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro375Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro375Arg change remains unknown at this time. (less)
|
|
Likely benign
(Apr 20, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
DICER1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004795607.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
click to load more submissions click to collapse |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor. | Kamihara J | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 32291395 |
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
DICER1 Mutations Are Frequent in Adolescent-Onset Papillary Thyroid Carcinoma. | Wasserman JD | The Journal of clinical endocrinology and metabolism | 2018 | PMID: 29474644 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/776daba8-46ba-4339-8fc1-22f854ce32fb | - | - | - | - |
Text-mined citations for rs148758903 ...
HelpRecord last updated May 25, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.