ClinVar Genomic variation as it relates to human health
NM_001987.5(ETV6):c.1106G>A (p.Arg369Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001987.5(ETV6):c.1106G>A (p.Arg369Gln)
Variation ID: 162221 Accession: VCV000162221.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.2 12: 11884541 (GRCh38) [ NCBI UCSC ] 12: 12037475 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 7, 2024 Mar 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001987.5:c.1106G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001978.1:p.Arg369Gln missense NC_000012.12:g.11884541G>A NC_000012.11:g.12037475G>A NG_011443.1:g.239688G>A LRG_609:g.239688G>A LRG_609t1:c.1106G>A LRG_609p1:p.Arg369Gln P41212:p.Arg369Gln - Protein change
- Other names
- R369Q
- Canonical SPDI
- NC_000012.12:11884540:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ETV6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
278 | 383 | |
LOC126861452 | - | - | - | GRCh38 | - | 54 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Nov 30, 2014 | RCV000149803.9 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2015 | RCV000157610.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 3, 2023 | RCV003162607.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 20, 2023 | RCV003372620.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2022 | RCV003415987.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 21, 2024 | RCV004526621.1 |
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. |
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Pathogenic
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003915053.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: negative effect on binding, altered subcellular localization, decreased transcriptional repression in a dominant-negative fashion, and impaired hematopoiesis (Zhang … (more)
Published functional studies demonstrate a damaging effect: negative effect on binding, altered subcellular localization, decreased transcriptional repression in a dominant-negative fashion, and impaired hematopoiesis (Zhang et al., 2015; Topka et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27663637, 26102509, 25581430, 26522332, 28555414, 29034503, 27365488, 28637624, 32841218) (less)
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Pathogenic
(Sep 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004295843.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with ETV6-related thrombocytopenia (PMID: 25581430). It has also been observed to segregate with disease in related individuals. … (more)
This missense change has been observed in individual(s) with ETV6-related thrombocytopenia (PMID: 25581430). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg369 amino acid residue in ETV6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26522332, 27365488, 31064749). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430). 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 expected to disrupt ETV6 protein function. ClinVar contains an entry for this variant (Variation ID: 162221). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 369 of the ETV6 protein (p.Arg369Gln). (less)
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Pathogenic
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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ETV6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115726.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ETV6 c.1106G>A variant is predicted to result in the amino acid substitution p.Arg369Gln. This variant has been reported in individuals with Thrombocytopenia and/or hematologic … (more)
The ETV6 c.1106G>A variant is predicted to result in the amino acid substitution p.Arg369Gln. This variant has been reported in individuals with Thrombocytopenia and/or hematologic malignancy (Zhang et al. 2015. PubMed ID: 25581430; Moriyama et al. 2015. PubMed ID: 26522332; Drazer et al. 2022. PubMed ID: 35537115). Functional study showed this variant abrogated DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis (Zhang et al. 2015. PubMed ID: 25581430). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted likely pathogenic. (less)
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Likely pathogenic
(Dec 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004087410.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.R369Q variant (also known as c.1106G>A), located in coding exon 6 of the ETV6 gene, results from a G to A substitution at nucleotide … (more)
The p.R369Q variant (also known as c.1106G>A), located in coding exon 6 of the ETV6 gene, results from a G to A substitution at nucleotide position 1106. The arginine at codon 369 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in multiple individuals with a personal and/or family history that is consistent with ETV6-related disease (Drazer MW et al. Blood Adv 2022 Aug;6(15):4357-4359; Moriyama T et al. Lancet Oncol 2015 Dec;16(16):1659-66; Leinøe E et al. Br J Haematol 2019 Jul;186(2):373-376). Multiple functional studies have demonstrated that this alteration impacts the ability of ETV6 to bind DNA and repress target gene function (Fisher MH et al. JCI Insight 2020 Sep;5(18); Topka S et al. PLoS Genet 2015 Jun;11(6):e1005262; Nishii R et al. Blood 2021 Jan;137(3):364-373). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Mar 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic acidemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039284.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
Variant summary: MUT c.1106G>A (p.Arg369His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha/beta chain, catalytic domain of the encoded protein … (more)
Variant summary: MUT c.1106G>A (p.Arg369His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha/beta chain, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250696 control chromosomes. c.1106G>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 30, 2014)
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no assertion criteria provided
Method: research
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thrombocytopenia
hematologic malignancy
Affected status: yes
Allele origin:
germline
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Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center
Accession: SCV000195554.1
First in ClinVar: Jan 18, 2015 Last updated: Jan 18, 2015 |
Number of individuals with the variant: 6
Sex: mixed
Ethnicity/Population group: Scottish
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Pathogenic
(Feb 01, 2015)
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no assertion criteria provided
Method: literature only
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THROMBOCYTOPENIA 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000207419.3
First in ClinVar: Feb 19, 2015 Last updated: Nov 04, 2016 |
Comment on evidence:
In 5 affected members of a family of Scottish descent with THC5 (616216), Zhang et al. (2015) identified a heterozygous c.1106G-A transition in the ETV6 … (more)
In 5 affected members of a family of Scottish descent with THC5 (616216), Zhang et al. (2015) identified a heterozygous c.1106G-A transition in the ETV6 gene, resulting in an arg369-to-gln (R369Q) substitution at a highly conserved residue in the second beta-sheet of the ETS DNA-binding domain. The mutation was not present in the dbSNP (build 139), 1000 Genomes Project, or Exome Variant Server databases. In vitro electrophoretic studies indicated that the mutation abrogated DNA binding, and functional studies showed that it lost normal transcriptional repression activity in a dominant-negative manner by interfering with homo-oligomerization. The mutant protein also showed reduced nuclear localization compared to wildtype and impaired hematopoiesis. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia. | Melazzini F | Haematologica | 2016 | PMID: 27365488 |
Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. | Moriyama T | The Lancet. Oncology | 2015 | PMID: 26522332 |
Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. | Topka S | PLoS genetics | 2015 | PMID: 26102509 |
Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. | Zhang MY | Nature genetics | 2015 | PMID: 25581430 |
ETV6 mutation in a cohort of 970 patients with hematologic malignancies. | Wang Q | Haematologica | 2014 | PMID: 24997145 |
ETV6 and signaling gene mutations are associated with secondary transformation of myelodysplastic syndromes to chronic myelomonocytic leukemia. | Padron E | Blood | 2014 | PMID: 24904105 |
Clinical effect of point mutations in myelodysplastic syndromes. | Bejar R | The New England journal of medicine | 2011 | PMID: 21714648 |
Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. | Zhang J | Blood | 2011 | PMID: 21680795 |
ETV6 mutations and loss in AML-M0. | Silva FP | Leukemia | 2008 | PMID: 18305557 |
Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. | Barjesteh van Waalwijk van Doorn-Khosrovani S | Oncogene | 2005 | PMID: 15806161 |
The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. | Wang LC | Genes & development | 1998 | PMID: 9694803 |
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Text-mined citations for rs724159946 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.