VCV000133885.17 - ClinVar

NM_004364.5(CEBPA):c.1009A>T (p.Thr337Ser)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004364.5(CEBPA):c.1009A>T (p.Thr337Ser)

Variation ID: 133885 Accession: VCV000133885.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.11 19: 33301406 (GRCh38) [ NCBI UCSC ] 19: 33792312 (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	Jun 9, 2014	Oct 8, 2024	Jun 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004364.5:c.1009A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004355.2:p.Thr337Ser	missense
NM_001285829.2:c.652A>T	NP_001272758.1:p.Thr218Ser	missense
NM_001287424.2:c.1114A>T	NP_001274353.1:p.Thr372Ser	missense
NM_001287435.2:c.967A>T	NP_001274364.1:p.Thr323Ser	missense
NC_000019.10:g.33301406T>A
NC_000019.9:g.33792312T>A
NG_012022.1:g.6119A>T
LRG_456:g.6119A>T
LRG_456t1:c.1009A>T

... more HGVS ... less HGVS

Protein change

T337S, T323S, T372S, T218S

Other names

Canonical SPDI

NC_000019.10:33301405:T:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA158088 dbSNP: rs587778192 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.
CEBPA		No evidence available	No evidence available	GRCh38 GRCh37	943	1015

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 specified	Uncertain significance (2)	criteria provided, single submitter	Jan 3, 2022	RCV000120549.6
Acute myeloid leukemia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 17, 2023	RCV000533682.11
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2024	RCV002472950.4

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.
Uncertain significance (Sep 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acute myeloid leukemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212549.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Jun 27, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002770236.3 First in ClinVar: Dec 31, 2022 Last updated: Oct 08, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31751678, 24728327, 28250006, 21455213) (less)
Uncertain significance (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002065351.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the CEBPA gene demonstrated a sequence change, c.1009A>T, in exon 1 that results in an amino acid change, p.Thr337Ser. This sequence … (more) DNA sequence analysis of the CEBPA gene demonstrated a sequence change, c.1009A>T, in exon 1 that results in an amino acid change, p.Thr337Ser. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the non-Finnish European subpopulation (dbSNP rs587778192). The p.Thr337Ser change affects a highly conserved amino acid residue located in a domain of the CEBPA protein that is known to be functional. The p.Thr337Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with CEBPA-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr337Ser change remains unknown at this time. (less)
Uncertain significance (Nov 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Acute myeloid leukemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000627077.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 28250006 Comment: This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 337 of the CEBPA protein (p.Thr337Ser). … (more) This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 337 of the CEBPA protein (p.Thr337Ser). This variant is present in population databases (rs587778192, gnomAD 0.005%). This missense change has been observed in individual(s) with acute myeloid leukemia, but the germline nature of this variant is unclear (PMID: 28250006). ClinVar contains an entry for this variant (Variation ID: 133885). 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 CEBPA protein function with a negative predictive value of 80%. 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)
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084703.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31751678, 24728327, 28250006, 21455213)

Comment:

DNA sequence analysis of the CEBPA gene demonstrated a sequence change, c.1009A>T, in exon 1 that results in an amino acid change, p.Thr337Ser. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the non-Finnish European subpopulation (dbSNP rs587778192). The p.Thr337Ser change affects a highly conserved amino acid residue located in a domain of the CEBPA protein that is known to be functional. The p.Thr337Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with CEBPA-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr337Ser change remains unknown at this time.

Comment:

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 337 of the CEBPA protein (p.Thr337Ser). This variant is present in population databases (rs587778192, gnomAD 0.005%). This missense change has been observed in individual(s) with acute myeloid leukemia, but the germline nature of this variant is unclear (PMID: 28250006). ClinVar contains an entry for this variant (Variation ID: 133885). 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 CEBPA protein function with a negative predictive value of 80%. 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
CEBPA-double-mutated acute myeloid leukemia displays a unique phenotypic profile: a reliable screening method and insight into biological features.	Mannelli F	Haematologica	2017	PMID: 28250006

Text-mined citations for rs587778192 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_004364.5(CEBPA):c.1009A>T (p.Thr337Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778192 ...