NC_000021.8:g.(?_36164432)_(37834775_?)del AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004579319.2

Allele description [Variation Report for NC_000021.8:g.(?_36164432)_(37834775_?)del]

NC_000021.8:g.(?_36164432)_(37834775_?)del

Genes:

DOP1B:DOP1 leucine zipper like protein B [Gene - OMIM - HGNC]
MORC3:MORC family CW-type zinc finger 3 [Gene - OMIM - HGNC]
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
SETD4:SET domain containing 4 [Gene - HGNC]
CBR1:carbonyl reductase 1 [Gene - OMIM - HGNC]
CBR3:carbonyl reductase 3 [Gene - OMIM - HGNC]
CHAF1B:chromatin assembly factor 1 subunit B [Gene - OMIM - HGNC]
CLDN14:claudin 14 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

21q22.12-22.13

Genomic location:

Chr21: 36164432 - 37834775 (on Assembly GRCh37)

Preferred name:

NC_000021.8:g.(?_36164432)_(37834775_?)del

HGVS:

NC_000021.8:g.(?_36164432)_(37834775_?)del

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
SCV005068068	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 18, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18723428, 24100448, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005068068

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 18, 2023)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.

Owen CJ, Toze CL, Koochin A, Forrest DL, Smith CA, Stevens JM, Jackson SC, Poon MC, Sinclair GD, Leber B, Johnson PR, Macheta A, Yin JA, Barnett MJ, Lister TA, Fitzgibbon J.

Blood. 2008 Dec 1;112(12):4639-45. doi: 10.1182/blood-2008-05-156745. Epub 2008 Aug 21.

PubMed [citation]

PMID:: 18723428

Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.

Stockley J, Morgan NV, Bem D, Lowe GC, Lordkipanidzé M, Dawood B, Simpson MA, Macfarlane K, Horner K, Leo VC, Talks K, Motwani J, Wilde JT, Collins PW, Makris M, Watson SP, Daly ME; UK Genotyping and Phenotyping of Platelets Study Group.

Blood. 2013 Dec 12;122(25):4090-3. doi: 10.1182/blood-2013-06-506873. Epub 2013 Oct 7.

PubMed [citation]

PMID:: 24100448
PMCID:: PMC3862284

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV005068068.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the RUNX1 gene has been identified. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes.

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

Last Updated: Sep 29, 2024

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