NM_001754.4(RUNX1):c.649G>A (p.Gly217Arg) AND Familial platelet disorder with associated myeloid malignancy

Clinical significance:Uncertain significance (Last evaluated: Aug 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000694237.4

Allele description [Variation Report for NM_001754.4(RUNX1):c.649G>A (p.Gly217Arg)]

NM_001754.4(RUNX1):c.649G>A (p.Gly217Arg)

Gene:
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.12
Genomic location:
Preferred name:
NM_001754.4(RUNX1):c.649G>A (p.Gly217Arg)
HGVS:
  • NC_000021.9:g.34834566C>T
  • NG_011402.2:g.1155146G>A
  • NM_001001890.3:c.568G>A
  • NM_001122607.2:c.568G>A
  • NM_001754.4:c.649G>A
  • NP_001001890.1:p.Gly190Arg
  • NP_001116079.1:p.Gly190Arg
  • NP_001745.2:p.Gly217Arg
  • LRG_482t1:c.649G>A
  • LRG_482:g.1155146G>A
  • LRG_482p1:p.Gly217Arg
  • NC_000021.8:g.36206863C>T
Protein change:
G190R
Links:
dbSNP: rs749004431
NCBI 1000 Genomes Browser:
rs749004431
Molecular consequence:
  • NM_001001890.3:c.568G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001122607.2:c.568G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001754.4:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000822672Invitaecriteria provided, single submitter
Uncertain significance
(Aug 24, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Childhood B-cell precursor acute lymphoblastic leukaemia in a patient with familial thrombocytopenia and RUNX1 mutation.

Linden T, Schnittger S, Groll AH, Juergens H, Rossig C.

Br J Haematol. 2010 Dec;151(5):528-30. doi: 10.1111/j.1365-2141.2010.08370.x. Epub 2010 Sep 29. No abstract available.

PubMed [citation]
PMID:
20880108

Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.

Drazer MW, Kadri S, Sukhanova M, Patil SA, West AH, Feurstein S, Calderon DA, Jones MF, Weipert CM, Daugherty CK, Ceballos-López AA, Raca G, Lingen MW, Li Z, Segal JP, Churpek JE, Godley LA.

Blood Adv. 2018 Jan 23;2(2):146-150. doi: 10.1182/bloodadvances.2017013037.

PubMed [citation]
PMID:
29365323
PMCID:
PMC5787862
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000822672.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glycine with arginine at codon 217 of the RUNX1 protein (p.Gly217Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs749004431, ExAC 0.01%). This variant has been reported in an individual affected with familial platelet disorder with B-cell precursor acute lymphoblastic leukemia (PMID: 20880108) and in an individual affected with hereditary hematopoietic malignancies (PMID: 29365323). This variant is also known as Gly190Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 436614). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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