NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg) AND Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 28, 2022
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:: RCV002281886.1

Allele description [Variation Report for NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg)]

NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg)

Gene:

DNMT3B:DNA methyltransferase 3 beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q11.21

Genomic location:

Preferred name:

NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg)

HGVS:

NC_000020.11:g.32807782A>G
NG_007290.1:g.50398A>G
NM_001207055.2:c.2066A>G
NM_001207056.2:c.1964A>G
NM_006892.4:c.2441A>GMANE SELECT
NM_175848.2:c.2381A>G
NM_175849.2:c.2192A>G
NM_175850.3:c.2417A>G
NP_001193984.1:p.His689Arg
NP_001193985.1:p.His655Arg
NP_008823.1:p.His814Arg
NP_008823.1:p.His814Arg
NP_787044.1:p.His794Arg
NP_787045.1:p.His731Arg
NP_787046.1:p.His806Arg
LRG_56t1:c.2441A>G
LRG_56:g.50398A>G
LRG_56p1:p.His814Arg
NC_000020.10:g.31395588A>G
NM_006892.3:c.2441A>G

Protein change:

H655R

Molecular consequence:

NM_001207055.2:c.2066A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001207056.2:c.1964A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006892.4:c.2441A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_175848.2:c.2381A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_175849.2:c.2192A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_175850.3:c.2417A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (ICF1)
Identifiers:: MONDO: MONDO:0009454; MedGen: C4551557; Orphanet: 2268; OMIM: 242860

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Dhx34 DExH-box helicase 34 [Mus musculus]
Dhx34 DExH-box helicase 34 [Mus musculus]
Gene ID:71723

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002572463	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 28, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15580563, 21549127, 11102980, 16543361 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002572463

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 28, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DNMT3B mutations and DNA methylation defect define two types of ICF syndrome.

Jiang YL, Rigolet M, Bourc'his D, Nigon F, Bokesoy I, Fryns JP, Hultén M, Jonveaux P, Maraschio P, Mégarbané A, Moncla A, Viegas-Péquignot E.

Hum Mutat. 2005 Jan;25(1):56-63.

PubMed [citation]

PMID:: 15580563

ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation.

Moarefi AH, Chédin F.

J Mol Biol. 2011 Jun 24;409(5):758-72. doi: 10.1016/j.jmb.2011.04.050. Epub 2011 Apr 27.

PubMed [citation]

PMID:: 21549127

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572463.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: DNMT3B c.2441A>G (p.His814Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251160 control chromosomes (gnomAD). c.2441A>G has been reported in the literature in at least two compound heterozygous individuals affected with ICF Syndrome (e.g. Wijmenga_2000, Jiang_2005). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Xie_2006, Moarefi_2011). The most pronounced effect of the variant results in approximately 2% methylation activity compared to the wild-type protein and disrupted homo-oligomerization and a severely impacted ability to bind SAM (Moarefi_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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