VCV000375884.5 - ClinVar

NM_022552.5(DNMT3A):c.2644C>A (p.Arg882Ser)

Germline

Classification

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.

(3)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022552.5(DNMT3A):c.2644C>A (p.Arg882Ser)

Variation ID: 375884 Accession: VCV000375884.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 25234374 (GRCh38) [ NCBI UCSC ] 2: 25457243 (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	Feb 28, 2024	Sep 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022552.5:c.2644C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_072046.2:p.Arg882Ser	missense
NM_001320893.1:c.2188C>A	NP_001307822.1:p.Arg730Ser	missense
NM_001375819.1:c.1975C>A	NP_001362748.1:p.Arg659Ser	missense
NM_153759.3:c.2077C>A	NP_715640.2:p.Arg693Ser	missense
NM_175629.2:c.2644C>A	NP_783328.1:p.Arg882Ser	missense
NR_135490.2:n.3074C>A		non-coding transcript variant
NC_000002.12:g.25234374G>T
NC_000002.11:g.25457243G>T
NG_029465.2:g.113217C>A
LRG_459:g.113217C>A
LRG_459t2:c.2077C>A	LRG_459p2:p.Arg693Ser
LRG_459t4:c.2644C>A	LRG_459p4:p.Arg882Ser

... more HGVS ... less HGVS

Protein change

R693S, R882S, R730S, R659S

Other names

Canonical SPDI

NC_000002.12:25234373:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA16602367 dbSNP: rs377577594 VarSome

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
Gene	OMIM	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		Little 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.
Acute myeloid leukemia	Pathogenic (1)	no assertion criteria provided	Oct 2, 2014	RCV000438614.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 18, 2020	RCV001782899.4
Tatton-Brown-Rahman overgrowth syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 20, 2023	RCV003766178.2

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.
Likely pathogenic (Dec 18, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017312.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Uncertain significance (Sep 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tatton-Brown-Rahman overgrowth syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004687897.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 34092059‚ 27317772‚ 28432085 Comment: This missense change has been observed in individual(s) with clinical features of Tatton-Brown-Rahman syndrome (PMID: 34092059). ClinVar contains an entry for this variant (Variation ID: … (more) This missense change has been observed in individual(s) with clinical features of Tatton-Brown-Rahman syndrome (PMID: 34092059). ClinVar contains an entry for this variant (Variation ID: 375884). 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. This variant disrupts the p.Arg882 amino acid residue in DNMT3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27317772, 28432085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 882 of the DNMT3A protein (p.Arg882Ser). (less)
Pathogenic (Oct 02, 2014)	no assertion criteria provided Method: literature only	Acute myeloid leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503767.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (5) PubMed: 22160010‚ 21067377‚ 22744846‚ 21518476‚ 22898540 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000264709:c.2644C>A

Comment:

This missense change has been observed in individual(s) with clinical features of Tatton-Brown-Rahman syndrome (PMID: 34092059). ClinVar contains an entry for this variant (Variation ID: 375884). 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. This variant disrupts the p.Arg882 amino acid residue in DNMT3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27317772, 28432085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 882 of the DNMT3A protein (p.Arg882Ser).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome.	Tovy A	Haematologica	2022	PMID: 34092059
Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.	Hollink IHIM	Journal of medical genetics	2017	PMID: 28432085
SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort.	Tlemsani C	Journal of medical genetics	2016	PMID: 27317772
Cancer stem cells: Tracing clones.	McCarthy N	Nature reviews. Cancer	2012	PMID: 22898540
Screening for mutation R882 in the DNMT3A gene in Chinese patients with hematological disease.	Li Y	International journal of hematology	2012	PMID: 22744846
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.2644C>A	-	-	-	-

Text-mined citations for rs377577594 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_022552.5(DNMT3A):c.2644C>A (p.Arg882Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377577594 ...