NM_006892.4(DNMT3B):c.2452G>A (p.Val818Met) AND Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 20, 2023
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:: RCV002512865.3

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:: Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (ICF1)
Synonyms:: ICF syndrome; Immunodeficiency syndrome, variable; Centromeric instability, immunodeficiency syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0000133; MedGen: C0398788; OMIM: PS242860

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003258178	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10647011, 11102980, 15580563, 11919202, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003258178

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 20, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

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

Genetic variation in ICF syndrome: evidence for genetic heterogeneity.

Wijmenga C, Hansen RS, Gimelli G, Björck EJ, Davies EG, Valentine D, Belohradsky BH, van Dongen JJ, Smeets DF, van den Heuvel LP, Luyten JA, Strengman E, Weemaes C, Pearson PL.

Hum Mutat. 2000 Dec;16(6):509-17. Review.

PubMed [citation]

PMID:: 11102980

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003258178.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 818 of the DNMT3B protein (p.Val818Met). This variant is present in population databases (rs121908940, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome (PMID: 10647011, 11102980, 15580563). This variant is also known as p.V810M. ClinVar contains an entry for this variant (Variation ID: 6734). 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 DNMT3B protein function. Experimental studies have shown that this missense change affects DNMT3B function (PMID: 11919202). For these reasons, this variant has been classified as 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: Nov 3, 2024

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