Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014); Reported as a hot spot location for somatic mutations in individuals with acute myeloid leukemia (AML), and thought to contribute to leukemogenesis by increasing CDK1 protein levels and enhancing cell-cycle activity (Xu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28667884, 30185810, 34788385, 24656771, 24497509, 27991732, 29349042, 29518238, 30245403, 28643785, 30017658, 28475857, 27701732, 28386848, 28941052, 31961069, 28252636)
ClinVar Genomic variation as it relates to human health
NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(19)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
19
criteria provided, multiple submitters, no conflicts
Somatic
Clinical impact
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate somatic clinical impact for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)
Variation ID: 375881 Accession: VCV000375881.51
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 25234373 (GRCh38) [ NCBI UCSC ] 2: 25457242 (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 Mar 8, 2017 Oct 8, 2024 Jun 25, 2024 Somatic - Clinical impact Mar 5, 2024 Mar 5, 2024 Jan 24, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_022552.5:c.2645G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_072046.2:p.Arg882His missense NM_001320893.1:c.2189G>A NP_001307822.1:p.Arg730His missense NM_001375819.1:c.1976G>A NP_001362748.1:p.Arg659His missense NM_022552.4:c.2645G>A NM_153759.3:c.2078G>A NP_715640.2:p.Arg693His missense NM_175629.2:c.2645G>A NP_783328.1:p.Arg882His missense NR_135490.2:n.3075G>A non-coding transcript variant NC_000002.12:g.25234373C>T NC_000002.11:g.25457242C>T NG_029465.2:g.113218G>A LRG_459:g.113218G>A LRG_459t2:c.2078G>A LRG_459p2:p.Arg693His LRG_459t4:c.2645G>A LRG_459p4:p.Arg882His - Protein change
- R693H, R882H, R730H, R659H
- Other names
- -
- Canonical SPDI
- NC_000002.12:25234372:C:T
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
- 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. |
|||
| DNMT3A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
762 | 818 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000418424.1 | |
| Pathogenic/Likely pathogenic (4) |
no assertion criteria provided
|
Jun 8, 2023 | RCV000430182.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437399.1 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 10, 2022 | RCV000485343.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 6, 2022 | RCV000623601.5 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2024 | RCV000524775.16 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001814155.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 25, 2024 | RCV002248654.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 11, 2020 | RCV004017608.1 | |
|
DNMT3A-related disorder
|
not provided (1) |
no classification provided
|
- | RCV004545768.1 |
|
EBV-positive nodal T- and NK-cell lymphoma
|
Pathogenic (1) |
no assertion criteria provided
|
- | RCV004559051.1 |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003153242.1 | |
| click to load more click to collapse | ||||
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566073.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability … (more)
Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014); Reported as a hot spot location for somatic mutations in individuals with acute myeloid leukemia (AML), and thought to contribute to leukemogenesis by increasing CDK1 protein levels and enhancing cell-cycle activity (Xu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28667884, 30185810, 34788385, 24656771, 24497509, 27991732, 29349042, 29518238, 30245403, 28643785, 30017658, 28475857, 27701732, 28386848, 28941052, 31961069, 28252636) (less)
|
|
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Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tatton-Brown-Rahman overgrowth syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000655299.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 882 of the DNMT3A protein (p.Arg882His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 882 of the DNMT3A protein (p.Arg882His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Tatton-Brown-Rahman overgrowth syndrome (PMID: 27991732, 28252636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375881). 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 DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 22722925, 24622842, 24656771, 26876596). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740689.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.2645G>A (p.R882H) alteration is located in exon 23 (coding exon 22) of the DNMT3A gene. This alteration results from a G to A substitution … (more)
The c.2645G>A (p.R882H) alteration is located in exon 23 (coding exon 22) of the DNMT3A gene. This alteration results from a G to A substitution at nucleotide position 2645, causing the arginine (R) at amino acid position 882 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.023% (64/282404) total alleles studied. The highest observed frequency was 0.055% (11/19926) of East Asian alleles. Additionally, this alteration has also been observed to occur sporadically in the population and proposed to be an early mutation in cancer initiation (Ley, 2010: Russler-Germain, 2014). Somatic mosaicism in individuals in general population databases cannot be ruled out. This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with clinical features of Tatton-Brown-Rahman syndrome, some of which later developed hematopoietic malignancies (Kosaki, 2017; Shen, 2017; Balci, 2020; Ferris, 2022; DECIPHER v.9.32). This alteration has been well described as a somatically acquired mutation associated with acute myeloid leukemia. It accounts for approximately 50% of all somatic DNMT3A mutations observed in AML cells (Ley, 2010, Russler-Germain, 2014). This nucleotide position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs DNA methyltransferase activity and results in hypomethylation at differentially-methylated regions within the genome (Russler-Germain, 2014; Emperle, 2018; Emperle, 2019; Nguyen, 2019; Norvil, 2020; Anteneh, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755336.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
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Pathogenic
(Apr 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tatton-Brown-Rahman overgrowth syndrome
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Accession: SCV004046512.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene was identified at low variant allele frequency (4/26 reads, 15%VAF), and may represent a low level … (more)
The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene was identified at low variant allele frequency (4/26 reads, 15%VAF), and may represent a low level mosaic germline variant or an acquired somatic variant. The c.2645G>A, p.(Arg882His) variant in the DNMT3A gene is a well known Pathogenic variant and has been identified in multiple individuals with Tatton-Brown-Rahman syndrome [PMID: 29900417, 27991732, 28941052, others], and is also often identified as a somatic variant in Acute Myeloid Leukemia cells [PMID:21067377, 24656771, 35771960, others]. Functional studies demonstrate that this variant impairs DNA methyltransferase activity resulting in hypomethylation of regions throughout the genome [PMID:31620784, 31582562, 32385248, others]. The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene is reported as Pathogenic. (less)
Clinical Features:
Aortic aneurysm (present) , Joint hypermobility (present) , Hernia (present) , Cataract (present)
Secondary finding: no
|
|
|
Likely pathogenic
(May 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003831553.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Mar 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tatton-Brown-Rahman overgrowth syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, CHRU Nancy
Accession: SCV004805247.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Testing laboratory: Organization ID: 506599
|
|
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Likely Pathogenic
(Aug 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848448.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg882His variant in DNMT3A has been reported in 2 heterozygous individuals (one de novo) with Tatton-Brown-Rahman syndrome, one of who also developed acute myelogenous … (more)
The p.Arg882His variant in DNMT3A has been reported in 2 heterozygous individuals (one de novo) with Tatton-Brown-Rahman syndrome, one of who also developed acute myelogenous leukemia (Kosaki 2018 PMID: 27991732, Hollink 2017 PMID: 28432085). It has been reported in ClinVar (Variation ID 375881) and identified in 0.055% (11/19926) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg882Cys) has been identified in 2 individuals (de novo) with Tatton-Brown-Rahman syndrome and this residue (Arg882) (including p.Arg882His) is the most frequent DNMT3A somatic mutation hotspot in AML (Tlemsani 2016 PMID: 27317772, Kosaki 2018 PMID: 27991732). In vitro functional studies further support an impact on protein function (Russler-Germain 2014 PMID: 24656771). It is possible that some DNMT3A variants may actually represent postzygotic clonal hematopoiesis rather than constitutional variants (see PMID 27546487; 25426838). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tatton-Brown-Rahman syndrome. ACMG/AMP Criteria applied: PS2, PP3, PM5, PS3_Supporting, PS4_Supporting. (less)
|
|
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Pathogenic
(Jun 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516987.2
First in ClinVar: May 28, 2022 Last updated: Jun 29, 2024 |
Comment:
This variant has been reported as a de novo event in multiple unrelated individuals with Tatton-Brown–Rahman syndrome, as well as other missense variant in the … (more)
This variant has been reported as a de novo event in multiple unrelated individuals with Tatton-Brown–Rahman syndrome, as well as other missense variant in the same residue (https://pubmed.ncbi.nlm.nih.gov/28941052/ ; https://pubmed.ncbi.nlm.nih.gov/34788385/). Codon 882 is considered a mutational hotspot for both somatic events in hematological neoplasias and for constitutional mutations leading to TBRS. Population data for this variant is unreliable as it might be the result of postzygotic clonal hematopoiesis Functional studies have demonstrated approximately 80% reduction of methyltransferase activity for this mutant (https://pubmed.ncbi.nlm.nih.gov/24656771/). Therefore we interpret it as pathogenic. (less)
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Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Myelodysplastic syndrome
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503761.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Acute myeloid leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503760.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503762.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Pathogenic
(Feb 16, 2023)
|
no assertion criteria provided
Method: literature only
|
TATTON-BROWN-RAHMAN SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000700192.4
First in ClinVar: Mar 26, 2018 Last updated: Mar 18, 2023 |
Comment on evidence:
Tatton-Brown-Rahman Syndrome In 2 unrelated patients with Tatton-Brown-Rahman syndrome (TBRS; 615879), Shen et al. (2017) identified a de novo heterozygous c.2645G-A transition (c.2645G-A, NM_175629.2) in … (more)
Tatton-Brown-Rahman Syndrome In 2 unrelated patients with Tatton-Brown-Rahman syndrome (TBRS; 615879), Shen et al. (2017) identified a de novo heterozygous c.2645G-A transition (c.2645G-A, NM_175629.2) in the DNMT3A gene, resulting in an R882H substitution. In a 6-year-old girl with TBRS, Kosaki et al. (2017) identified heterozygosity for the de novo R882H mutation in the DNMT3A gene. Acute Myeloid Leukemia, Somatic Of 62 patients with acute myelogenous leukemia (AML; 601626) who were found to have a somatic mutation in the DNMT3A gene, Ley et al. (2010) found that 27 had a C-to-T transition at a CpG dinucleotide, resulting in an arg882-to-his (R882H) substitution. Functional Studies of DNMT3A R882H Using size-exclusion chromatography, Nguyen et al. (2019) confirmed that human DNMT3A formed large oligomeric species, as well as smaller complexes around the size of a tetramer, with large oligomers having lower methyltransferase activity relative to smaller complexes. The dominant-negative DNMT3A R882H mutant stabilized DNMT3A oligomer formation and shifted the DNMT3A oligomer equilibrium toward higher-order multimers, resulting in a dose-dependent reduction of enzyme activity compared with wildtype DNMT3A. In contrast, mutations that disrupted the oligomer-forming interface of the DNMT3A catalytic domain caused a significant shift from large oligomers to smaller species, with reduced enzymatic activity relative to wildtype and comparable with that of R882H. DNMT3L (606588) disrupted formation of large oligomers to activate wildtype DNMT3A by binding to and breaking down higher-order DNMT3A into smaller, more active complexes. Likewise, DNMT3L bound to the R882H mutant, but activity of the R882H mutant was only partially restored relative to wildtype DNMT3A, suggesting that R882H interferes with DNMT3A methyltransferase activity by an additional mechanism. Further analysis revealed that the R882H mutation also compromised the DNA-binding ability of DNMT3A. Sandoval and Reich (2019) found that wildtype DNMT3A and the DNMT3A R882H mutant were differentially responsive to modulation by p53 (TP53; 191170), as p53 failed to inhibit methylation activity of DNMT3A R882H. Using purified recombinant proteins, Norvil et al. (2020) showed that DNMT3A R882 mutants lost the cooperative kinetic mechanism in methylation of DNA substrates compared with wildtype DNMT3A. R882 played a key role in the interaction of DNMT3A with DNA, and the R882H mutation altered the specificity of DNMT3A such that it adopted a substrate preference similar to that of DNMT3B (602900), making DNMT3A R882H a DNMT3B-like enzyme. The authors noted that DNMT3A and DNMT3B redundantly methylate many genomic regions in cells, but they also have preferred and specific targets, as Dnmt3a preferentially methylates major satellite repeats in pericentric regions in mouse cells, whereas Dnmt3b preferentially methylates minor satellite repeats in centromeric regions. Analysis with mouse embryonic stem cells revealed that mouse Dnmt3a R878H mutant retained activity for minor satellite DNA and methylated Dnmt3b-preferred target sites but lost its preference for sites methylated by Dnmt3a. (less)
|
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Pathogenic
(Feb 16, 2023)
|
no assertion criteria provided
Method: literature only
|
LEUKEMIA, ACUTE MYELOID, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000700193.4
First in ClinVar: Mar 26, 2018 Last updated: Mar 18, 2023 |
Comment on evidence:
Tatton-Brown-Rahman Syndrome In 2 unrelated patients with Tatton-Brown-Rahman syndrome (TBRS; 615879), Shen et al. (2017) identified a de novo heterozygous c.2645G-A transition (c.2645G-A, NM_175629.2) in … (more)
Tatton-Brown-Rahman Syndrome In 2 unrelated patients with Tatton-Brown-Rahman syndrome (TBRS; 615879), Shen et al. (2017) identified a de novo heterozygous c.2645G-A transition (c.2645G-A, NM_175629.2) in the DNMT3A gene, resulting in an R882H substitution. In a 6-year-old girl with TBRS, Kosaki et al. (2017) identified heterozygosity for the de novo R882H mutation in the DNMT3A gene. Acute Myeloid Leukemia, Somatic Of 62 patients with acute myelogenous leukemia (AML; 601626) who were found to have a somatic mutation in the DNMT3A gene, Ley et al. (2010) found that 27 had a C-to-T transition at a CpG dinucleotide, resulting in an arg882-to-his (R882H) substitution. Functional Studies of DNMT3A R882H Using size-exclusion chromatography, Nguyen et al. (2019) confirmed that human DNMT3A formed large oligomeric species, as well as smaller complexes around the size of a tetramer, with large oligomers having lower methyltransferase activity relative to smaller complexes. The dominant-negative DNMT3A R882H mutant stabilized DNMT3A oligomer formation and shifted the DNMT3A oligomer equilibrium toward higher-order multimers, resulting in a dose-dependent reduction of enzyme activity compared with wildtype DNMT3A. In contrast, mutations that disrupted the oligomer-forming interface of the DNMT3A catalytic domain caused a significant shift from large oligomers to smaller species, with reduced enzymatic activity relative to wildtype and comparable with that of R882H. DNMT3L (606588) disrupted formation of large oligomers to activate wildtype DNMT3A by binding to and breaking down higher-order DNMT3A into smaller, more active complexes. Likewise, DNMT3L bound to the R882H mutant, but activity of the R882H mutant was only partially restored relative to wildtype DNMT3A, suggesting that R882H interferes with DNMT3A methyltransferase activity by an additional mechanism. Further analysis revealed that the R882H mutation also compromised the DNA-binding ability of DNMT3A. Sandoval and Reich (2019) found that wildtype DNMT3A and the DNMT3A R882H mutant were differentially responsive to modulation by p53 (TP53; 191170), as p53 failed to inhibit methylation activity of DNMT3A R882H. Using purified recombinant proteins, Norvil et al. (2020) showed that DNMT3A R882 mutants lost the cooperative kinetic mechanism in methylation of DNA substrates compared with wildtype DNMT3A. R882 played a key role in the interaction of DNMT3A with DNA, and the R882H mutation altered the specificity of DNMT3A such that it adopted a substrate preference similar to that of DNMT3B (602900), making DNMT3A R882H a DNMT3B-like enzyme. The authors noted that DNMT3A and DNMT3B redundantly methylate many genomic regions in cells, but they also have preferred and specific targets, as Dnmt3a preferentially methylates major satellite repeats in pericentric regions in mouse cells, whereas Dnmt3b preferentially methylates minor satellite repeats in centromeric regions. Analysis with mouse embryonic stem cells revealed that mouse Dnmt3a R878H mutant retained activity for minor satellite DNA and methylated Dnmt3b-preferred target sites but lost its preference for sites methylated by Dnmt3a. (less)
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|
|
Likely pathogenic
(Aug 06, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Acute myeloid leukemia
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011716.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Clonal Cytopenia of Undetermined Significance
Affected status: unknown
Allele origin:
somatic
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Molecular Genetic Pathology Unit, University Of Rochester Medical Center
Accession: SCV003840278.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
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Pathogenic
(Jun 08, 2023)
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no assertion criteria provided
Method: clinical testing
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Acute myeloid leukemia
Affected status: yes
Allele origin:
somatic
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Sung Lab, Department of Medicine, Roswell Park Comprehensive Cancer Center
Accession: SCV003932620.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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EBV-positive nodal T- and NK-cell lymphoma
Affected status: yes
Allele origin:
unknown
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Department of Clinical Pathology, School of Medicine, Fujita Health University
Accession: SCV004217903.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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DNMT3A-related disorder
Affected status: unknown
Allele origin:
de novo
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GenomeConnect - Brain Gene Registry
Accession: SCV002760016.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Variant interpreted as Uncertain significance and reported on 04-14-2015 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient … (more)
Variant interpreted as Uncertain significance and reported on 04-14-2015 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Generalized hypotonia (present) , Neurodevelopmental delay (present) , Hyperostosis (present) , Chiari malformation (present) , Cryptorchidism (present) , Micropenis (present) , Pes planus (present) , … (more)
Generalized hypotonia (present) , Neurodevelopmental delay (present) , Hyperostosis (present) , Chiari malformation (present) , Cryptorchidism (present) , Micropenis (present) , Pes planus (present) , 2-3 toe syndactyly (present) , Broad hallux (present) , Aplasia/Hypoplasia involving the pelvis (present) , Abnormal facial shape (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-04-14
Testing laboratory interpretation: Uncertain significance
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Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 882 of the DNMT3A protein (p.Arg882His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Tatton-Brown-Rahman overgrowth syndrome (PMID: 27991732, 28252636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375881). 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 DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 22722925, 24622842, 24656771, 26876596). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.2645G>A (p.R882H) alteration is located in exon 23 (coding exon 22) of the DNMT3A gene. This alteration results from a G to A substitution at nucleotide position 2645, causing the arginine (R) at amino acid position 882 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.023% (64/282404) total alleles studied. The highest observed frequency was 0.055% (11/19926) of East Asian alleles. Additionally, this alteration has also been observed to occur sporadically in the population and proposed to be an early mutation in cancer initiation (Ley, 2010: Russler-Germain, 2014). Somatic mosaicism in individuals in general population databases cannot be ruled out. This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with clinical features of Tatton-Brown-Rahman syndrome, some of which later developed hematopoietic malignancies (Kosaki, 2017; Shen, 2017; Balci, 2020; Ferris, 2022; DECIPHER v.9.32). This alteration has been well described as a somatically acquired mutation associated with acute myeloid leukemia. It accounts for approximately 50% of all somatic DNMT3A mutations observed in AML cells (Ley, 2010, Russler-Germain, 2014). This nucleotide position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs DNA methyltransferase activity and results in hypomethylation at differentially-methylated regions within the genome (Russler-Germain, 2014; Emperle, 2018; Emperle, 2019; Nguyen, 2019; Norvil, 2020; Anteneh, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene was identified at low variant allele frequency (4/26 reads, 15%VAF), and may represent a low level mosaic germline variant or an acquired somatic variant. The c.2645G>A, p.(Arg882His) variant in the DNMT3A gene is a well known Pathogenic variant and has been identified in multiple individuals with Tatton-Brown-Rahman syndrome [PMID: 29900417, 27991732, 28941052, others], and is also often identified as a somatic variant in Acute Myeloid Leukemia cells [PMID:21067377, 24656771, 35771960, others]. Functional studies demonstrate that this variant impairs DNA methyltransferase activity resulting in hypomethylation of regions throughout the genome [PMID:31620784, 31582562, 32385248, others]. The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene is reported as Pathogenic.
Comment:
The p.Arg882His variant in DNMT3A has been reported in 2 heterozygous individuals (one de novo) with Tatton-Brown-Rahman syndrome, one of who also developed acute myelogenous leukemia (Kosaki 2018 PMID: 27991732, Hollink 2017 PMID: 28432085). It has been reported in ClinVar (Variation ID 375881) and identified in 0.055% (11/19926) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg882Cys) has been identified in 2 individuals (de novo) with Tatton-Brown-Rahman syndrome and this residue (Arg882) (including p.Arg882His) is the most frequent DNMT3A somatic mutation hotspot in AML (Tlemsani 2016 PMID: 27317772, Kosaki 2018 PMID: 27991732). In vitro functional studies further support an impact on protein function (Russler-Germain 2014 PMID: 24656771). It is possible that some DNMT3A variants may actually represent postzygotic clonal hematopoiesis rather than constitutional variants (see PMID 27546487; 25426838). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tatton-Brown-Rahman syndrome. ACMG/AMP Criteria applied: PS2, PP3, PM5, PS3_Supporting, PS4_Supporting.
Comment:
This variant has been reported as a de novo event in multiple unrelated individuals with Tatton-Brown–Rahman syndrome, as well as other missense variant in the same residue (https://pubmed.ncbi.nlm.nih.gov/28941052/ ; https://pubmed.ncbi.nlm.nih.gov/34788385/). Codon 882 is considered a mutational hotspot for both somatic events in hematological neoplasias and for constitutional mutations leading to TBRS. Population data for this variant is unreliable as it might be the result of postzygotic clonal hematopoiesis Functional studies have demonstrated approximately 80% reduction of methyltransferase activity for this mutant (https://pubmed.ncbi.nlm.nih.gov/24656771/). Therefore we interpret it as pathogenic.
Comment:
This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation.
Comment:
Variant interpreted as Uncertain significance and reported on 04-14-2015 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
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. |
Comment:
Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014); Reported as a hot spot location for somatic mutations in individuals with acute myeloid leukemia (AML), and thought to contribute to leukemogenesis by increasing CDK1 protein levels and enhancing cell-cycle activity (Xu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28667884, 30185810, 34788385, 24656771, 24497509, 27991732, 29349042, 29518238, 30245403, 28643785, 30017658, 28475857, 27701732, 28386848, 28941052, 31961069, 28252636)
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 882 of the DNMT3A protein (p.Arg882His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Tatton-Brown-Rahman overgrowth syndrome (PMID: 27991732, 28252636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375881). 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 DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 22722925, 24622842, 24656771, 26876596). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.2645G>A (p.R882H) alteration is located in exon 23 (coding exon 22) of the DNMT3A gene. This alteration results from a G to A substitution at nucleotide position 2645, causing the arginine (R) at amino acid position 882 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.023% (64/282404) total alleles studied. The highest observed frequency was 0.055% (11/19926) of East Asian alleles. Additionally, this alteration has also been observed to occur sporadically in the population and proposed to be an early mutation in cancer initiation (Ley, 2010: Russler-Germain, 2014). Somatic mosaicism in individuals in general population databases cannot be ruled out. This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with clinical features of Tatton-Brown-Rahman syndrome, some of which later developed hematopoietic malignancies (Kosaki, 2017; Shen, 2017; Balci, 2020; Ferris, 2022; DECIPHER v.9.32). This alteration has been well described as a somatically acquired mutation associated with acute myeloid leukemia. It accounts for approximately 50% of all somatic DNMT3A mutations observed in AML cells (Ley, 2010, Russler-Germain, 2014). This nucleotide position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs DNA methyltransferase activity and results in hypomethylation at differentially-methylated regions within the genome (Russler-Germain, 2014; Emperle, 2018; Emperle, 2019; Nguyen, 2019; Norvil, 2020; Anteneh, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene was identified at low variant allele frequency (4/26 reads, 15%VAF), and may represent a low level mosaic germline variant or an acquired somatic variant. The c.2645G>A, p.(Arg882His) variant in the DNMT3A gene is a well known Pathogenic variant and has been identified in multiple individuals with Tatton-Brown-Rahman syndrome [PMID: 29900417, 27991732, 28941052, others], and is also often identified as a somatic variant in Acute Myeloid Leukemia cells [PMID:21067377, 24656771, 35771960, others]. Functional studies demonstrate that this variant impairs DNA methyltransferase activity resulting in hypomethylation of regions throughout the genome [PMID:31620784, 31582562, 32385248, others]. The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene is reported as Pathogenic.
Comment:
The p.Arg882His variant in DNMT3A has been reported in 2 heterozygous individuals (one de novo) with Tatton-Brown-Rahman syndrome, one of who also developed acute myelogenous leukemia (Kosaki 2018 PMID: 27991732, Hollink 2017 PMID: 28432085). It has been reported in ClinVar (Variation ID 375881) and identified in 0.055% (11/19926) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg882Cys) has been identified in 2 individuals (de novo) with Tatton-Brown-Rahman syndrome and this residue (Arg882) (including p.Arg882His) is the most frequent DNMT3A somatic mutation hotspot in AML (Tlemsani 2016 PMID: 27317772, Kosaki 2018 PMID: 27991732). In vitro functional studies further support an impact on protein function (Russler-Germain 2014 PMID: 24656771). It is possible that some DNMT3A variants may actually represent postzygotic clonal hematopoiesis rather than constitutional variants (see PMID 27546487; 25426838). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tatton-Brown-Rahman syndrome. ACMG/AMP Criteria applied: PS2, PP3, PM5, PS3_Supporting, PS4_Supporting.
Comment:
This variant has been reported as a de novo event in multiple unrelated individuals with Tatton-Brown–Rahman syndrome, as well as other missense variant in the same residue (https://pubmed.ncbi.nlm.nih.gov/28941052/ ; https://pubmed.ncbi.nlm.nih.gov/34788385/). Codon 882 is considered a mutational hotspot for both somatic events in hematological neoplasias and for constitutional mutations leading to TBRS. Population data for this variant is unreliable as it might be the result of postzygotic clonal hematopoiesis Functional studies have demonstrated approximately 80% reduction of methyltransferase activity for this mutant (https://pubmed.ncbi.nlm.nih.gov/24656771/). Therefore we interpret it as pathogenic.
Comment:
This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation.
Comment:
Variant interpreted as Uncertain significance and reported on 04-14-2015 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. | Ferris MA | Blood | 2022 | PMID: 34788385 |
| Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. | Anteneh H | Nature communications | 2020 | PMID: 32385248 |
| The acute myeloid leukemia variant DNMT3A Arg882His is a DNMT3B-like enzyme. | Norvil AB | Nucleic acids research | 2020 | PMID: 32123902 |
| Tatton-Brown-Rahman syndrome: Six individuals with novel features. | Balci TB | American journal of medical genetics. Part A | 2020 | PMID: 31961069 |
| The R882H substitution in the human de novo DNA methyltransferase DNMT3A disrupts allosteric regulation by the tumor supressor p53. | Sandoval JE | The Journal of biological chemistry | 2019 | PMID: 31640986 |
| Mutations of R882 change flanking sequence preferences of the DNA methyltransferase DNMT3A and cellular methylation patterns. | Emperle M | Nucleic acids research | 2019 | PMID: 31620784 |
| The R882H DNMT3A hot spot mutation stabilizes the formation of large DNMT3A oligomers with low DNA methyltransferase activity. | Nguyen TV | The Journal of biological chemistry | 2019 | PMID: 31582562 |
| The DNMT3A R882H mutation does not cause dominant negative effects in purified mixed DNMT3A/R882H complexes. | Emperle M | Scientific reports | 2018 | PMID: 30185810 |
| The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies. | Shen W | American journal of medical genetics. Part A | 2017 | PMID: 28941052 |
| The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. | Baldridge D | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28252636 |
| Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. | Kosaki R | American journal of medical genetics. Part A | 2017 | PMID: 27991732 |
| DNMT3A(R882H) mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice. | Scourzic L | Leukemia | 2016 | PMID: 26876596 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. | Russler-Germain DA | Cancer cell | 2014 | PMID: 24656771 |
| Driver mutations of cancer epigenomes. | Roy DM | Protein & cell | 2014 | PMID: 24622842 |
| Molecular evaluation of DNMT3A and IDH1/2 gene mutation: frequency, distribution pattern and associations with additional molecular markers in normal karyotype Indian acute myeloid leukemia patients. | Ahmad F | Asian Pacific journal of cancer prevention : APJCP | 2014 | PMID: 24606448 |
| The role of mutations in epigenetic regulators in myeloid malignancies. | Shih AH | Nature reviews. Cancer | 2012 | PMID: 22898539 |
| Screening for mutation R882 in the DNMT3A gene in Chinese patients with hematological disease. | Li Y | International journal of hematology | 2012 | PMID: 22744846 |
| Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. | Holz-Schietinger C | The Journal of biological chemistry | 2012 | PMID: 22722925 |
| Impact of genetic features on treatment decisions in AML. | Döhner H | Hematology. American Society of Hematology. Education Program | 2011 | PMID: 22160010 |
| [Analysis of DNMT3a gene mutations in acute myelogenous leukemia]. | Qiao C | Zhongguo shi yan xue ye xue za zhi | 2011 | PMID: 21518476 |
| DNMT3A mutations in acute myeloid leukemia. | Ley TJ | The New England journal of medicine | 2010 | PMID: 21067377 |
| http://docm.genome.wustl.edu/variants/ENST00000264709:c.2645G>A | - | - | - | - |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
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Tier II (Potential)
- prognostic
- poor outcome
(1)
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Jan 24, 2024 | RCV000430182.9 | ||
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Oncogenic
criteria provided, single submitter
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Jul 31, 2024 | RCV004668919.1 |
Submissions - Somatic
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Clinical impact
Help
The submitted somatic clinical impact 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Tier II (Potential)
- Prognostic
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poor outcome (Jan 24, 2024)
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no assertion criteria provided
Method: clinical testing
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Acute myeloid leukemia
Affected status: unknown
Allele origin:
somatic
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Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health
Accession: SCV004697534.1
First In ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
Comment:
This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation.
Clinical Features:
Bone marrow hypercellularity (present) , Granulocytic hyperplasia (present)
Age: 70-79 years
Sex: female
Tissue: peripheral blood with 5% CD34/CD117-positive myeloblasts
Comment on evidence:
The patient was treated with 5-azyctadine for hypercellular bone marrow with 5-9% blasts; however, five months later, a bone marrow biopsy showed 37% blasts positive … (more)
The patient was treated with 5-azyctadine for hypercellular bone marrow with 5-9% blasts; however, five months later, a bone marrow biopsy showed 37% blasts positive for CD33, CD34, CD117, and HLA-DR, consistent with AML, and a novel translocation t(4;7)(q12;q21.2). After induction chemotherapy with cytarabine and daunorubicin, a day-14 biopsy showed response to therapy. Following eight months of complete remission, the patient developed a relapse of AML. Flow cytometry of peripheral blood demonstrated 5% CD34/CD117-positive myeloblasts. The myeloid population displayed dysgranulopoiesis indicative of hypogranulation, and aberrant CD56 coexpression in a myelomonocytic subpopulation. Karyotype analysis detected the same t(4;7) translocation. Chromosome microarray testing indicated copy neutral loss of heterozygosity of 21q11.1qter and loss of a small segment in band 2p13.1 in 100% of the DNA from a blood sample. Blood RNA NGS analysis detected AKAP9::PDGFRA fusion transcripts consistent with the translocation. Additional somatic mutations were detected at AML relapse; a RUNX1 p.Arg162Lys variant was homozygous due to the LOH of 21q containing the RUNX1 locus at 21q22.12. Heterozygous somatic mutations of note were WT1 p.Arg462Leu (42% allele frequency), DNMT3A p.Arg882His (46%), and MYC p.Thr73Ala (47%). (less)
Method: Average 800x coverage of all exons from 275 cancer-related genes.
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Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Oncogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm
Affected status: unknown
Allele origin:
somatic
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094253.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Comment:
Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014); Reported as a hot spot location for somatic mutations in individuals with acute myeloid leukemia (AML), and thought to contribute to leukemogenesis by increasing CDK1 protein levels and enhancing cell-cycle activity (Xu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28667884, 30185810, 34788385, 24656771, 24497509, 27991732, 29349042, 29518238, 30245403, 28643785, 30017658, 28475857, 27701732, 28386848, 28941052, 31961069, 28252636)
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 882 of the DNMT3A protein (p.Arg882His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Tatton-Brown-Rahman overgrowth syndrome (PMID: 27991732, 28252636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375881). 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 DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 22722925, 24622842, 24656771, 26876596). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.2645G>A (p.R882H) alteration is located in exon 23 (coding exon 22) of the DNMT3A gene. This alteration results from a G to A substitution at nucleotide position 2645, causing the arginine (R) at amino acid position 882 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.023% (64/282404) total alleles studied. The highest observed frequency was 0.055% (11/19926) of East Asian alleles. Additionally, this alteration has also been observed to occur sporadically in the population and proposed to be an early mutation in cancer initiation (Ley, 2010: Russler-Germain, 2014). Somatic mosaicism in individuals in general population databases cannot be ruled out. This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with clinical features of Tatton-Brown-Rahman syndrome, some of which later developed hematopoietic malignancies (Kosaki, 2017; Shen, 2017; Balci, 2020; Ferris, 2022; DECIPHER v.9.32). This alteration has been well described as a somatically acquired mutation associated with acute myeloid leukemia. It accounts for approximately 50% of all somatic DNMT3A mutations observed in AML cells (Ley, 2010, Russler-Germain, 2014). This nucleotide position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs DNA methyltransferase activity and results in hypomethylation at differentially-methylated regions within the genome (Russler-Germain, 2014; Emperle, 2018; Emperle, 2019; Nguyen, 2019; Norvil, 2020; Anteneh, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene was identified at low variant allele frequency (4/26 reads, 15%VAF), and may represent a low level mosaic germline variant or an acquired somatic variant. The c.2645G>A, p.(Arg882His) variant in the DNMT3A gene is a well known Pathogenic variant and has been identified in multiple individuals with Tatton-Brown-Rahman syndrome [PMID: 29900417, 27991732, 28941052, others], and is also often identified as a somatic variant in Acute Myeloid Leukemia cells [PMID:21067377, 24656771, 35771960, others]. Functional studies demonstrate that this variant impairs DNA methyltransferase activity resulting in hypomethylation of regions throughout the genome [PMID:31620784, 31582562, 32385248, others]. The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene is reported as Pathogenic.
Comment:
The p.Arg882His variant in DNMT3A has been reported in 2 heterozygous individuals (one de novo) with Tatton-Brown-Rahman syndrome, one of who also developed acute myelogenous leukemia (Kosaki 2018 PMID: 27991732, Hollink 2017 PMID: 28432085). It has been reported in ClinVar (Variation ID 375881) and identified in 0.055% (11/19926) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg882Cys) has been identified in 2 individuals (de novo) with Tatton-Brown-Rahman syndrome and this residue (Arg882) (including p.Arg882His) is the most frequent DNMT3A somatic mutation hotspot in AML (Tlemsani 2016 PMID: 27317772, Kosaki 2018 PMID: 27991732). In vitro functional studies further support an impact on protein function (Russler-Germain 2014 PMID: 24656771). It is possible that some DNMT3A variants may actually represent postzygotic clonal hematopoiesis rather than constitutional variants (see PMID 27546487; 25426838). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tatton-Brown-Rahman syndrome. ACMG/AMP Criteria applied: PS2, PP3, PM5, PS3_Supporting, PS4_Supporting.
Comment:
This variant has been reported as a de novo event in multiple unrelated individuals with Tatton-Brown–Rahman syndrome, as well as other missense variant in the same residue (https://pubmed.ncbi.nlm.nih.gov/28941052/ ; https://pubmed.ncbi.nlm.nih.gov/34788385/). Codon 882 is considered a mutational hotspot for both somatic events in hematological neoplasias and for constitutional mutations leading to TBRS. Population data for this variant is unreliable as it might be the result of postzygotic clonal hematopoiesis Functional studies have demonstrated approximately 80% reduction of methyltransferase activity for this mutant (https://pubmed.ncbi.nlm.nih.gov/24656771/). Therefore we interpret it as pathogenic.
Comment:
This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation.
Comment:
Variant interpreted as Uncertain significance and reported on 04-14-2015 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia. | Gaidzik VI | Leukemia | 2018 | PMID: 28643785 |
| Association between DNMT3A mutations and prognosis of adults with de novo acute myeloid leukemia: a systematic review and meta-analysis. | Tie R | PloS one | 2014 | PMID: 24936645 |
| Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). | Gaidzik VI | Blood | 2013 | PMID: 23632886 |
| Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. | Marcucci G | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22291079 |
| Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. | Thol F | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21670448 |
| DNMT3A mutations in acute myeloid leukemia. | Ley TJ | The New England journal of medicine | 2010 | PMID: 21067377 |
Text-mined citations for rs147001633 ...
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Record last updated Nov 10, 2024
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.