NM_006892.4(DNMT3B):c.2452G>A (p.Val818Met) AND Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 27, 2017
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:: RCV000007126.9

Allele description [Variation Report for NM_006892.4(DNMT3B):c.2452G>A (p.Val818Met)]

NM_006892.4(DNMT3B):c.2452G>A (p.Val818Met)

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.2452G>A (p.Val818Met)

HGVS:

NC_000020.11:g.32807793G>A
NG_007290.1:g.50409G>A
NM_001207055.2:c.2077G>A
NM_001207056.2:c.1975G>A
NM_006892.4:c.2452G>AMANE SELECT
NM_175848.2:c.2392G>A
NM_175849.2:c.2203G>A
NM_175850.3:c.2428G>A
NP_001193984.1:p.Val693Met
NP_001193985.1:p.Val659Met
NP_008823.1:p.Val818Met
NP_787044.1:p.Val798Met
NP_787045.1:p.Val735Met
NP_787046.1:p.Val810Met
LRG_56t1:c.2452G>A
LRG_56:g.50409G>A
NC_000020.10:g.31395599G>A
NM_006892.3:c.2452G>A
Q9UBC3:p.Val818Met

Protein change:

V659M; VAL810MET

Links:

UniProtKB: Q9UBC3#VAR_011504; OMIM: 602900.0002; dbSNP: rs121908940

NCBI 1000 Genomes Browser:

rs121908940

Molecular consequence:

NM_001207055.2:c.2077G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001207056.2:c.1975G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006892.4:c.2452G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175848.2:c.2392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175849.2:c.2203G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175850.3:c.2428G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027322	OMIM	no assertion criteria provided	Pathogenic (Nov 11, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000914952	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Jul 27, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11919202, 10647011, 11102980, 15580563 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000027322

OMIM

no assertion criteria provided

Pathogenic
(Nov 11, 1999)

germline

literature only

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

SCV000914952

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Jul 27, 2017)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases.

Gowher H, Jeltsch A.

J Biol Chem. 2002 Jun 7;277(23):20409-14. Epub 2002 Mar 27.

PubMed [citation]

PMID:: 11919202

Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.

Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Péquignot E.

Nature. 1999 Nov 11;402(6758):187-91.

PubMed [citation]

PMID:: 10647011

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000027322.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with ICF syndrome (ICF1; 242860), Xu et al. (1999) identified a homozygous valine-to-methionine substitution at codon 810 (V810M) of the DNMT3B gene product. Each of the patient's consanguineous parents was heterozygous for this mutation.

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

From Illumina Laboratory Services, Illumina, SCV000914952.1

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

Description

The DNMT3B c.2452G>A (p.Val818Met) variant, also referred to as p.Val810Met, has been reported in three studies and is found in four individuals, two with the variant in a homozygous state and two with the variant in a compound heterozygous. All individuals were diagnosed with immunodeficiency-centromeric instability-facial anomalies syndrome (Xu et al. 1999; Wijmenga et al. 2000; Jiang et al. 2005). The parents of one homozygous individual were confirmed to be unaffected heterozygous carriers (Xu et al. 1999). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Val818Met variant is present in a catalytic domain. Gowher and Jeltsch (2002) used site directed mutagenesis of murine cDNA to generate variant protein which was evaluated to quantify the effect on catalytic activity. The rate of DNA methylation of classical satellites was found to be <10% of wild type. A second study that used patient leukocyte or fibroblast cultures also noted hypomethylation of the classical satellites, whereas the alpha satellites had methylation comparable to wild type (Jiang et al. 2005). Based on the collective evidence, the p.Val818Met variant is classified as pathogenic for immunodeficiency-centromeric instability-facial anomalies syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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: Jun 23, 2024

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