VCV000546858.31 - ClinVar

NM_022552.5(DNMT3A):c.2141C>G (p.Ser714Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022552.5(DNMT3A):c.2141C>G (p.Ser714Cys)

Variation ID: 546858 Accession: VCV000546858.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 25240672 (GRCh38) [ NCBI UCSC ] 2: 25463541 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 9, 2018	Oct 20, 2024	Sep 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022552.5:c.2141C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_072046.2:p.Ser714Cys	missense
NM_001320893.1:c.1685C>G	NP_001307822.1:p.Ser562Cys	missense
NM_001375819.1:c.1472C>G	NP_001362748.1:p.Ser491Cys	missense
NM_153759.3:c.1574C>G	NP_715640.2:p.Ser525Cys	missense
NM_175629.2:c.2141C>G	NP_783328.1:p.Ser714Cys	missense
NR_135490.2:n.2372C>G		non-coding transcript variant
NC_000002.12:g.25240672G>C
NC_000002.11:g.25463541G>C
NG_029465.2:g.106919C>G
LRG_459:g.106919C>G
LRG_459t2:c.1574C>G	LRG_459p2:p.Ser525Cys
LRG_459t4:c.2141C>G	LRG_459p4:p.Ser714Cys

... more HGVS ... less HGVS

Protein change

S525C, S714C, S562C, S491C

Other names

Canonical SPDI

NC_000002.12:25240671:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

dbSNP: rs367909007 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DNMT3A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	762	818

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2017	RCV000658860.23
Tatton-Brown-Rahman overgrowth syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Sep 30, 2023	RCV001251185.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tatton-Brown-Rahman overgrowth syndrome Affected status: yes Allele origin: de novo	Centogene AG - the Rare Disease Company Accession: SCV001426543.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 32860008
Uncertain significance (Sep 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tatton-Brown-Rahman overgrowth syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004292063.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28475857‚ 32860008‚ 30705090‚ 31861499 Comment: This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 714 of the DNMT3A protein … (more) This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 714 of the DNMT3A protein (p.Ser714Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Tatton-Brown-Rahman syndrome (PMID: 28475857, 32860008). ClinVar contains an entry for this variant (Variation ID: 546858). 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 not expected to disrupt DNMT3A protein function. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 30705090, 31861499). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000780657.29 First in ClinVar: Jul 09, 2018 Last updated: Oct 20, 2024	Number of individuals with the variant: 2

Comment:

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 714 of the DNMT3A protein (p.Ser714Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Tatton-Brown-Rahman syndrome (PMID: 28475857, 32860008). ClinVar contains an entry for this variant (Variation ID: 546858). 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 not expected to disrupt DNMT3A protein function. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 30705090, 31861499). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia.	Khrabrova DA	Biomolecules	2019	PMID: 31861499
Mutations in the DNMT3A DNA methyltransferase in acute myeloid leukemia patients cause both loss and gain of function and differential regulation by protein partners.	Sandoval JE	The Journal of biological chemistry	2019	PMID: 30705090
Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.	Tatton-Brown K	American journal of human genetics	2017	PMID: 28475857

Text-mined citations for rs367909007 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_022552.5(DNMT3A):c.2141C>G (p.Ser714Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs367909007 ...