NM_022552.5(DNMT3A):c.905G>C (p.Gly302Ala) AND Heyn-Sproul-Jackson syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 22, 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:: RCV003228061.8

Allele description [Variation Report for NM_022552.5(DNMT3A):c.905G>C (p.Gly302Ala)]

NM_022552.5(DNMT3A):c.905G>C (p.Gly302Ala)

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.905G>C (p.Gly302Ala)

HGVS:

NC_000002.12:g.25247700C>G
NG_029465.2:g.99891G>C
NM_001320893.1:c.449G>C
NM_001375819.1:c.236G>C
NM_022552.5:c.905G>CMANE SELECT
NM_153759.3:c.338G>C
NM_175629.2:c.905G>C
NP_001307822.1:p.Gly150Ala
NP_001362748.1:p.Gly79Ala
NP_072046.2:p.Gly302Ala
NP_715640.2:p.Gly113Ala
NP_783328.1:p.Gly302Ala
LRG_459t1:c.905G>C
LRG_459t2:c.338G>C
LRG_459t4:c.905G>C
LRG_459:g.99891G>C
LRG_459p2:p.Gly113Ala
LRG_459p4:p.Gly302Ala
NC_000002.11:g.25470569C>G
NM_022552.4:c.905G>C
NR_135490.2:n.1136G>C

Protein change:

G113A

Links:

dbSNP: rs1674986110

NCBI 1000 Genomes Browser:

rs1674986110

Molecular consequence:

NM_001320893.1:c.449G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375819.1:c.236G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_022552.5:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153759.3:c.338G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_175629.2:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_135490.2:n.1136G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

gain_of_function_variant [Sequence Ontology: SO:0002053]

Condition(s)

Name:: Heyn-Sproul-Jackson syndrome
Synonyms:: MICROCEPHALY, SHORT STATURE, AND IMPAIRED INTELLECTUAL DEVELOPMENT
Identifiers:: MONDO: MONDO:0032882; MedGen: C5231475; OMIM: 618724

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002547278	Wangler Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 22, 2022)	unknown	research	PubMed (3) [See all records that cite these PMIDs] 29740169, 33182397, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002547278

Wangler Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 22, 2022)

unknown

research

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
African American	unknown	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Gain-of-function mutations in DNMT3A in patients with paraganglioma.

Remacha L, Currás-Freixes M, Torres-Ruiz R, Schiavi F, Torres-Pérez R, Calsina B, Letón R, Comino-Méndez I, Roldán-Romero JM, Montero-Conde C, Santos M, Pérez LI, Pita G, Alonso MR, Honrado E, Pedrinaci S, Crespo-Facorro B, Percesepe A, Falcioni M, Rodríguez-Perales S, Korpershoek E, Ramón-Maiques S, et al.

Genet Med. 2018 Dec;20(12):1644-1651. doi: 10.1038/s41436-018-0003-y. Epub 2018 May 8.

PubMed [citation]

PMID:: 29740169

Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.

Mellid S, Coloma J, Calsina B, Monteagudo M, Roldán-Romero JM, Santos M, Leandro-García LJ, Lanillos J, Martínez-Montes ÁM, Rodríguez-Antona C, Montero-Conde C, Martínez-López J, Ayala R, Matias-Guiu X, Robledo M, Cascón A.

Cancers (Basel). 2020 Nov 9;12(11). doi: 10.3390/cancers12113304.

PubMed [citation]

PMID:: 33182397
PMCID:: PMC7697455

See all PubMed Citations (3)

Details of each submission

From Wangler Lab, Baylor College of Medicine, SCV002547278.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African American	1	not provided	not provided	research	PubMed (3)

Description

This missense variant at c.905G>C (p.G302A) in DNMT3A is located in the hotspot in the PWWP domain (PM1). This change has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD: 26.600)(PP3). The evolutionary conservation of this residue is high. Missense variants in nearby residues (p.K299I, p.R318W, p.G332R) have been reported in affected individuals (PMID:29740169, 33182397). We presume this variant to be de novo, though only the maternal sample was able to be obtained (PM6). We predict this variant to be likely pathogenic.

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

Last Updated: Nov 24, 2024

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