Submissions for variant NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)

dbSNP: rs147001633

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485343	SCV000566073	pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524775	SCV000655299	pathogenic	Tatton-Brown-Rahman overgrowth syndrome	2024-01-17	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000623601	SCV000740689	pathogenic	Inborn genetic diseases	2022-10-06	criteria provided, single submitter	clinical testing	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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814155	SCV001755336	likely pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Mendelics	RCV002248654	SCV002516987	pathogenic	not specified	2024-06-25	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000485343	SCV003831553	likely pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000524775	SCV004046512	pathogenic	Tatton-Brown-Rahman overgrowth syndrome	2023-04-13	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017608	SCV004848448	likely pathogenic	Intellectual disability	2020-08-11	criteria provided, single submitter	clinical testing	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.
Database of Curated Mutations (DoCM)	RCV000430182	SCV000503760	pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437399	SCV000503761	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418424	SCV000503762	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
OMIM	RCV000524775	SCV000700192	pathogenic	Tatton-Brown-Rahman overgrowth syndrome	2023-02-16	no assertion criteria provided	literature only
OMIM	RCV000430182	SCV000700193	pathogenic	Acute myeloid leukemia	2023-02-16	no assertion criteria provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000430182	SCV002011716	likely pathogenic	Acute myeloid leukemia	2021-08-06	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV004545768	SCV002760016	not provided	DNMT3A-related disorder		no assertion provided	phenotyping only	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/.
Molecular Genetic Pathology Unit, University Of Rochester Medical Center	RCV003153242	SCV003840278	pathogenic	Clonal Cytopenia of Undetermined Significance		no assertion criteria provided	clinical testing
Sung Lab, Department of Medicine, Roswell Park Comprehensive Cancer Center	RCV000430182	SCV003932620	pathogenic	Acute myeloid leukemia	2023-06-08	no assertion criteria provided	clinical testing
Department of Clinical Pathology, School of Medicine, Fujita Health University	RCV004559051	SCV004217903	pathogenic	EBV-positive nodal T- and NK-cell lymphoma		no assertion criteria provided	research