VCV000162222.15 - ClinVar

NM_001987.5(ETV6):c.641C>T (p.Pro214Leu)

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.

(9)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001987.5(ETV6):c.641C>T (p.Pro214Leu)

Variation ID: 162222 Accession: VCV000162222.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.2 12: 11869601 (GRCh38) [ NCBI UCSC ] 12: 12022535 (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	Jan 18, 2015	Feb 14, 2024	Aug 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001987.5:c.641C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001978.1:p.Pro214Leu	missense
NC_000012.12:g.11869601C>T
NC_000012.11:g.12022535C>T
NG_011443.1:g.224748C>T
LRG_609:g.224748C>T
LRG_609t1:c.641C>T	LRG_609p1:p.Pro214Leu
	P41212:p.Pro214Leu

... more HGVS ... less HGVS

Protein change

Other names

P214L

Canonical SPDI

NC_000012.12:11869600:C:T

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.

Links

ClinGen: CA175031 UniProtKB: P41212#VAR_073322 OMIM: 600618.0005 dbSNP: rs724159947 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.
ETV6		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	303	411

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.
Hematologic neoplasm Thrombocytopenia	Likely pathogenic (1)	no assertion criteria provided	Nov 30, 2014	RCV000149804.9
Thrombocytopenia 5	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 20, 2023	RCV000157611.24
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 24, 2023	RCV001818340.14
Acute myeloid leukemia	not provided (1)	no classification provided	-	RCV001281572.10

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.
Pathogenic (Aug 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002065858.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the ETV6 gene demonstrated a sequence change, c.641C>T, in exon 5 that results in an amino acid change, p.Pro214Leu. This pathogenic … (more) DNA sequence analysis of the ETV6 gene demonstrated a sequence change, c.641C>T, in exon 5 that results in an amino acid change, p.Pro214Leu. This pathogenic sequence change has previously been described in multiple individuals with ETV6-related thrombocytopenia and has been shown to segregate with disease in at least two families (PMID: 25581430, 25807284, 27663637, 31704777, 32367453). Additionally, experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284, 32367453). This sequence change has not been described in population databases including gnomAD (dbSNP rs724159947). The p.Pro214Leu change affects a highly conserved amino acid residue located in a domain of the ETV6 protein that is known to be functional. The p.Pro214Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggest that, the c.641C>T change is pathogenic. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombocytopenia 5 Affected status: yes Allele origin: germline	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002573466.2 First in ClinVar: Sep 17, 2022 Last updated: Jul 22, 2023 Comment: Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology	Clinical Features: Macrpthrombocytopenia (present)
Likely pathogenic (Jun 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombocytopenia 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175267.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (3) PubMed: 25581430‚ 25807284‚ 27666367 Comment: The ETV6 c.641C>T variant is classified as Likely Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PP1_Moderate) The ETV6 c.641C>T variant is a single nucleotide change in exon 5/8 … (more) The ETV6 c.641C>T variant is classified as Likely Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PP1_Moderate) The ETV6 c.641C>T variant is a single nucleotide change in exon 5/8 of the ETV6 gene, which is predicted to change the amino acid proline at position 214 in the protein to leucine. Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284). The p.Pro214Leu variant affects a highly conserved amino acid residue located in a linker inhibitory domain (amino acids 127–331) that indirectly promotes DNA binding (PS3_Supporting). The variant has been reported in multiple unrelated proband(s) with a clinical presentation of Thrombocytopenia. In addition, this variant has been reported in a patient subsequently developing a T cell/myloid mixed phenotype acute leukemia (MPAL) (PMID:25581430) (PS4_Moderate).This variant is absent from population databases (PM2). This variant co-segregates with disease demonstrated in PMID:27666367 which noted four generations of affected family members. (PP1_moderate). The variant has been reported in dbSNP (rs724159947) and in the HGMD database: CM150819. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162222). (less)
Pathogenic (Aug 31, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Thrombocytopenia 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764686.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Thrombocytopenia (present) , Atopic eczema (present)
Pathogenic (Aug 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440969.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 25581430‚ 25807284‚ 31704777‚ 33768492 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 214 of the ETV6 protein (p.Pro214Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 214 of the ETV6 protein (p.Pro214Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial thrombocytopenia with leukemia (PMID: 25581430, 25807284, 31704777, 33768492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162222). 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 ETV6 protein function. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 25807284). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 2015)	no assertion criteria provided Method: literature only	THROMBOCYTOPENIA 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000207420.3 First in ClinVar: Feb 19, 2015 Last updated: Nov 04, 2016	Publications: PubMed (2) PubMed: 25581430‚ 25807284 Comment on evidence: In an African American woman with thrombocytopenia-5 (THC5; 616216) who developed mixed T-cell/myeloid acute leukemia, Zhang et al. (2015) identified a heterozygous c.641C-T transition in … (more) In an African American woman with thrombocytopenia-5 (THC5; 616216) who developed mixed T-cell/myeloid acute leukemia, Zhang et al. (2015) identified a heterozygous c.641C-T transition in the ETV6 gene, resulting in a pro214-to-leu (P214L) substitution at a highly conserved residue in a linker inhibitory domain that indirectly promotes DNA binding. The mutation was not present in the dbSNP (build 139), 1000 Genomes Project, or Exome Variant Server databases. Expression of the mutation in HeLa cells showed that the mutant protein had predominantly cytoplasmic localization, rather than normal nuclear localization. The mutant protein also impaired hematopoiesis. In affected members of a family with THC5, Noetzli et al. (2015) identified heterozygosity for the c.641C-T transition (c.641C-T, NM_001987) in the ETV6 gene, resulting in a P214L substitution. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Direct screening of the ETV6 gene in 23 additional families with autosomal dominant thrombocytopenia identified 1 family with the same P214L mutation. Three patients from the 2 families developed B-cell leukemia. In vitro functional expression studies showed that the P214L mutant protein had less transcriptional repression activity than wildtype. Transfection of the mutation into CD34+ cells cultured with thrombopoietin resulted in delayed and decreased megakaryocyte maturation compared to control cells. There was aberrant cytoplasmic localization of both the mutant and wildtype protein, consistent with a dominant-negative effect. (less)
Pathogenic (Oct 14, 2021)	no assertion criteria provided Method: clinical testing	Thrombocytopenia 5 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002029215.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Likely pathogenic (Nov 30, 2014)	no assertion criteria provided Method: research	thrombocytopenia hematologic malignancy Affected status: yes Allele origin: germline	Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center Accession: SCV000195555.1 First in ClinVar: Jan 18, 2015 Last updated: Jan 18, 2015	Publications: PubMed (1) PubMed: 25581430 Number of individuals with the variant: 1 Sex: mixed Ethnicity/Population group: African-American
not provided (-)	no classification provided Method: literature only	Acute myeloid leukemia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001468882.2 First in ClinVar: Jan 17, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 33226740‚ 31248877 BookShelf: NBK564234 BookShelf: NBK564234

Comment:

DNA sequence analysis of the ETV6 gene demonstrated a sequence change, c.641C>T, in exon 5 that results in an amino acid change, p.Pro214Leu. This pathogenic sequence change has previously been described in multiple individuals with ETV6-related thrombocytopenia and has been shown to segregate with disease in at least two families (PMID: 25581430, 25807284, 27663637, 31704777, 32367453). Additionally, experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284, 32367453). This sequence change has not been described in population databases including gnomAD (dbSNP rs724159947). The p.Pro214Leu change affects a highly conserved amino acid residue located in a domain of the ETV6 protein that is known to be functional. The p.Pro214Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggest that, the c.641C>T change is pathogenic.

Comment:

The ETV6 c.641C>T variant is classified as Likely Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PP1_Moderate) The ETV6 c.641C>T variant is a single nucleotide change in exon 5/8 of the ETV6 gene, which is predicted to change the amino acid proline at position 214 in the protein to leucine. Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284). The p.Pro214Leu variant affects a highly conserved amino acid residue located in a linker inhibitory domain (amino acids 127–331) that indirectly promotes DNA binding (PS3_Supporting). The variant has been reported in multiple unrelated proband(s) with a clinical presentation of Thrombocytopenia. In addition, this variant has been reported in a patient subsequently developing a T cell/myloid mixed phenotype acute leukemia (MPAL) (PMID:25581430) (PS4_Moderate).This variant is absent from population databases (PM2). This variant co-segregates with disease demonstrated in PMID:27666367 which noted four generations of affected family members. (PP1_moderate). The variant has been reported in dbSNP (rs724159947) and in the HGMD database: CM150819. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162222).

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 214 of the ETV6 protein (p.Pro214Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial thrombocytopenia with leukemia (PMID: 25581430, 25807284, 31704777, 33768492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162222). 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 ETV6 protein function. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 25807284). For these reasons, this variant has been classified as Pathogenic.

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
ETV6-related thrombocytopenia associated with a transient decrease in von Willebrand factor.	Kanamaru Y	International journal of hematology	2021	PMID: 33768492
Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor.	Karastaneva A	Journal of medical genetics	2020	PMID: 31704777
ETV6-related thrombocytopenia and leukemia predisposition.	Di Paola J	Blood	2019	PMID: 31248877
Development of an electrochemical detection system for measuring DNA methylation levels using methyl CpG-binding protein and glucose dehydrogenase-fused zinc finger protein.	Lee J	Biosensors & bioelectronics	2017	PMID: 27666367
Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.	Noetzli L	Nature genetics	2015	PMID: 25807284
Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.	Zhang MY	Nature genetics	2015	PMID: 25581430

Text-mined citations for rs724159947 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001987.5(ETV6):c.641C>T (p.Pro214Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs724159947 ...