NM_022552.5(DNMT3A):c.2609del (p.Phe870fs) AND Tatton-Brown-Rahman overgrowth syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 7, 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:: RCV003746055.2

Allele description [Variation Report for NM_022552.5(DNMT3A):c.2609del (p.Phe870fs)]

NM_022552.5(DNMT3A):c.2609del (p.Phe870fs)

Gene:

DNMT3A:DNA methyltransferase 3 alpha [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_022552.5(DNMT3A):c.2609del (p.Phe870fs)

HGVS:

NC_000002.12:g.25234411del
NG_029465.2:g.113182del
NM_001320893.1:c.2153del
NM_001375819.1:c.1940del
NM_022552.5:c.2609delMANE SELECT
NM_153759.3:c.2042del
NM_175629.2:c.2609del
NP_001307822.1:p.Phe718fs
NP_001362748.1:p.Phe647fs
NP_072046.2:p.Phe870Serfs
NP_072046.2:p.Phe870fs
NP_715640.2:p.Phe681fs
NP_783328.1:p.Phe870fs
LRG_459t1:c.2607del
LRG_459t2:c.2042del
LRG_459t4:c.2609del
LRG_459:g.113182del
LRG_459p1:p.Phe870Serfs
LRG_459p2:p.Phe681fs
LRG_459p4:p.Phe870fs
NC_000002.11:g.25457278del
NC_000002.11:g.25457280del
NM_022552.4:c.2607delT
NR_135490.2:n.3039del

Protein change:

F647fs

Molecular consequence:

NM_001320893.1:c.2153del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375819.1:c.1940del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_022552.5:c.2609del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_153759.3:c.2042del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_175629.2:c.2609del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_135490.2:n.3039del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Tatton-Brown-Rahman overgrowth syndrome
Synonyms:: Tatton-Brown-rahman syndrome; Tall stature-intellectual disability-facial dysmorphism syndrome
Identifiers:: MONDO: MONDO:0014382; MedGen: C4014545; Orphanet: 404443; OMIM: 615879

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004452065	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27317772, 28432085, 31620784, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004452065

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 7, 2023)

germline

clinical testing

PubMed (4)
[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

SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort.

Tlemsani C, Luscan A, Leulliot N, Bieth E, Afenjar A, Baujat G, Doco-Fenzy M, Goldenberg A, Lacombe D, Lambert L, Odent S, Pasche J, Sigaudy S, Buffet A, Violle-Poirsier C, Briand-Suleau A, Laurendeau I, Chin M, Saugier-Veber P, Vidaud D, Cormier-Daire V, Vidaud M, et al.

J Med Genet. 2016 Nov;53(11):743-751. doi: 10.1136/jmedgenet-2015-103638. Epub 2016 Jun 17.

PubMed [citation]

PMID:: 27317772

Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.

Hollink IHIM, van den Ouweland AMW, Beverloo HB, Arentsen-Peters STCJM, Zwaan CM, Wagner A.

J Med Genet. 2017 Dec;54(12):805-808. doi: 10.1136/jmedgenet-2017-104574. Epub 2017 Apr 21. Review.

PubMed [citation]

PMID:: 28432085

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004452065.1

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

Description

This sequence change creates a premature translational stop signal (p.Phe870Serfs*11) in the DNMT3A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the DNMT3A protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DNMT3A protein in which other variant(s) (p.Arg882Cys) have been determined to be pathogenic (PMID: 27317772, 28432085, 31620784). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with DNMT3A-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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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