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NM_001754.5(RUNX1):c.749G>A (p.Arg250His) AND Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Germline classification:
Likely benign (1 submission)
Last evaluated:
Jun 24, 2024
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:
RCV004595499.1

Allele description [Variation Report for NM_001754.5(RUNX1):c.749G>A (p.Arg250His)]

NM_001754.5(RUNX1):c.749G>A (p.Arg250His)

Gene:
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.12
Genomic location:
Preferred name:
NM_001754.5(RUNX1):c.749G>A (p.Arg250His)
Other names:
NM_001754.5(RUNX1):c.749G>A
HGVS:
  • NC_000021.9:g.34834466C>T
  • NG_011402.2:g.1155246G>A
  • NM_001001890.3:c.668G>A
  • NM_001122607.2:c.668G>A
  • NM_001754.5:c.749G>AMANE SELECT
  • NP_001001890.1:p.Arg223His
  • NP_001116079.1:p.Arg223His
  • NP_001745.2:p.Arg250His
  • NP_001745.2:p.Arg250His
  • LRG_482t1:c.749G>A
  • LRG_482:g.1155246G>A
  • LRG_482p1:p.Arg250His
  • NC_000021.8:g.36206763C>T
  • NM_001754.4:c.749G>A
Protein change:
R223H
Links:
dbSNP: rs771614642
NCBI 1000 Genomes Browser:
rs771614642
Molecular consequence:
  • NM_001001890.3:c.668G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001122607.2:c.668G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001754.5:c.749G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Identifiers:
MONDO: MONDO:0011071; MedGen: CN281654

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005088376ClinGen Myeloid Malignancy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v2)		Likely Benign
(Jun 24, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV005088376.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.749G>A variant in RUNX1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 250 (p.R250H). A luciferase reporter assaying in U937 cells showed that this variant has normal transcriptional activity, and an EMSA assay using COS7 cells showed that this variant has normal DNA-binding and β-subunit interaction with normal nuclear localization in NIH3T3 cells, indicating that this variant does not impact protein function (PMID: 23817177) (BS3). The computational predictor, REVEL, gives a score of 0.488, which is below the threshold of 0.50, evidence that suggests no impact on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS3 and BP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024