NM_001754.5(RUNX1):c.497G>A (p.Arg166Gln) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 30, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000477937.11

Allele description

NM_001754.5(RUNX1):c.497G>A (p.Arg166Gln)

Genes:

RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
RUNX1-AS1:RUNX1 antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_001754.5(RUNX1):c.497G>A (p.Arg166Gln)

Other names:

NM_001754.4(RUNX1):c.497G>A

HGVS:

NC_000021.9:g.34880568C>T
NG_011402.2:g.1109144G>A
NM_001001890.3:c.416G>A
NM_001122607.2:c.416G>A
NM_001754.5:c.497G>AMANE SELECT
NP_001001890.1:p.Arg139Gln
NP_001116079.1:p.Arg139Gln
NP_001745.2:p.Arg166Gln
NP_001745.2:p.Arg166Gln
LRG_482t1:c.497G>A
LRG_482:g.1109144G>A
LRG_482p1:p.Arg166Gln
NC_000021.8:g.36252865C>T
NM_001754.4:c.497G>A
p.Arg166Gln

Protein change:

R139Q

Links:

dbSNP: rs1060499616

NCBI 1000 Genomes Browser:

rs1060499616

Molecular consequence:

NM_001001890.3:c.416G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.416G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.497G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Synonyms:: Platelet disorder, Aspirin-like; Familial platelet disorder with associated myeloid malignancy; Familial Platelet Disorder with Propensity to Acute Myelogenous Leukemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0100083; MeSH: C563324; MedGen: C1832388; Orphanet: 71290; OMIM: 601399

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000536928	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Mar 6, 2016)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV000965620	ClinGen Myeloid Malignancy Variant Curation Expert Panel	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v1)	Pathogenic (Jul 30, 2019)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 25840971, 26175287, 11830488, 10508512, 28960434, 23848403 Citation Link,
SCV001575463	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 10508512, 26175287, 27210295, 28960434, 11830488, 22012064, 23848403, 26916619, 31048839, 11049997, 12002768, 22318203, 25840971, 28492532
SCV002569218	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.

Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, et al.

Nat Genet. 1999 Oct;23(2):166-75.

PubMed [citation]

PMID:: 10508512

Analyses of Genetic and Clinical Parameters for Screening Patients With Inherited Thrombocytopenia with Small or Normal-Sized Platelets.

Ouchi-Uchiyama M, Sasahara Y, Kikuchi A, Goi K, Nakane T, Ikeno M, Noguchi Y, Uike N, Miyajima Y, Matsubara K, Koh K, Sugita K, Imaizumi M, Kure S.

Pediatr Blood Cancer. 2015 Dec;62(12):2082-8. doi: 10.1002/pbc.25668. Epub 2015 Jul 14.

PubMed [citation]

PMID:: 26175287

See all PubMed Citations (15)

Details of each submission

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536928.1

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

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

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV000965620.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.497G>A (p.Arg166Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBF-beta binding and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 10508512, 28960434, 26175287). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has a REVEL score >0.75 (0.962) (PP3). There are two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 8960434, 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PS4_Moderate, PM2, PP3, PM6_Supporting, PP1.

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

From Invitae, SCV001575463.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 166 of the RUNX1 protein (p.Arg166Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia, myelodysplastic syndrome and/or acute myeloid leukemia (PMID: 10508512, 26175287, 27210295, 28960434). It has also been observed to segregate with disease in related individuals. This variant is also known as c.416G>A. ClinVar contains an entry for this variant (Variation ID: 417961). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 11830488, 22012064, 23848403, 25840971, 26916619, 31048839). This variant disrupts the p.Arg166 amino acid residue in RUNX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11049997, 12002768, 22318203, 25840971). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002569218.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

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

Last Updated: May 7, 2024

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