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NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His) AND Intellectual disability

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 11, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004017608.1

Allele description [Variation Report for NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)]

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

Gene:
DNMT3A:DNA methyltransferase 3 alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p23.3
Genomic location:
Preferred name:
NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)
HGVS:
  • NC_000002.12:g.25234373C>T
  • NG_029465.2:g.113218G>A
  • NM_001320893.1:c.2189G>A
  • NM_001375819.1:c.1976G>A
  • NM_022552.5:c.2645G>AMANE SELECT
  • NM_153759.3:c.2078G>A
  • NM_175629.2:c.2645G>A
  • NP_001307822.1:p.Arg730His
  • NP_001362748.1:p.Arg659His
  • NP_072046.2:p.Arg882His
  • NP_715640.2:p.Arg693His
  • NP_783328.1:p.Arg882His
  • LRG_459t2:c.2078G>A
  • LRG_459t4:c.2645G>A
  • LRG_459:g.113218G>A
  • LRG_459p2:p.Arg693His
  • LRG_459p4:p.Arg882His
  • NC_000002.11:g.25457242C>T
  • NM_022552.4:c.2645G>A
  • NM_022552.5:c.2645G>A
  • NM_175629.1:c.2645G>A
  • NR_135490.2:n.3075G>A
Protein change:
R659H; ARG882HIS
Links:
OMIM: 602769.0006; dbSNP: rs147001633
NCBI 1000 Genomes Browser:
rs147001633
Molecular consequence:
  • NM_001320893.1:c.2189G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375819.1:c.1976G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_022552.5:c.2645G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153759.3:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_175629.2:c.2645G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_135490.2:n.3075G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Intellectual disability
Synonyms:
Intellectual functioning disability; intellectual disabilities; Intellectual developmental disorder
Identifiers:
MONDO: MONDO:0001071; MeSH: D008607; MedGen: C3714756; Human Phenotype Ontology: HP:0001249

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004848448Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Aug 11, 2020) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848448.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024