NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys) AND Glanzmann thrombasthenia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 15, 2023
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:: RCV000778500.9

Allele description [Variation Report for NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys)]

NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys)

Gene:

ITGB3:integrin subunit beta 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.32

Genomic location:

Preferred name:

NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys)

HGVS:

NC_000017.11:g.47283375C>T
NG_008332.2:g.34534C>T
NM_000212.3:c.187C>TMANE SELECT
NP_000203.2:p.Arg63Cys
NP_000203.2:p.Arg63Cys
LRG_481t1:c.187C>T
LRG_481:g.34534C>T
LRG_481p1:p.Arg63Cys
NC_000017.10:g.45360741C>T
NM_000212.2:c.187C>T

Protein change:

R63C

Links:

dbSNP: rs199866795

NCBI 1000 Genomes Browser:

rs199866795

Molecular consequence:

NM_000212.3:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glanzmann thrombasthenia
Synonyms:: PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY; Thrombasthenia of Glanzmann and Naegeli; Glanzmann thrombasthenia type A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0100326; MedGen: C0040015; Orphanet: 849; OMIM: PS273800

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Epidermolysis bullosa dystrophica inversa, autosomal recessive
Epidermolysis bullosa dystrophica inversa, autosomal recessive

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914771	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001397580	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen Platelet ACMG Specifications v2-1)	Likely pathogenic (Aug 15, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000914771

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001397580

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2-1)

Likely pathogenic
(Aug 15, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

Nurden AT, Pillois X, Fiore M, Alessi MC, Bonduel M, Dreyfus M, Goudemand J, Gruel Y, Benabdallah-Guerida S, Latger-Cannard V, Négrier C, Nugent D, Oiron RD, Rand ML, Sié P, Trossaert M, Alberio L, Martins N, Sirvain-Trukniewicz P, Couloux A, Canault M, Fronthroth JP, et al.

Hum Mutat. 2015 May;36(5):548-61. doi: 10.1002/humu.22776.

PubMed [citation]

PMID:: 25728920

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914771.1

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

Description

The ITGB3 c.187C>T (p.Arg63Cys) variant has been reported in one study and was found in a compound heterozygous state with a nonsense variant in one patient with Glanzmann thrombasthenia, type II (Nurden et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. When the p.Arg63Cys-containing integrin was transiently expressed in COS-7 cells, Î±IIbÎ²3 protein expression was reduced by 85% compared to wild type. Immunoblotting of lysed cells from the patient also showed that pro-Î±IIb and mature Î±IIb expression was reduced, indicating that Î±IIbÎ²3 complex maturation was slowed or impaired. Based on the evidence, the p.Arg63Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for thrombasthenia of Glanzmann and Naegeli. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV001397580.3

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

Description

The missense variant, NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys), has been reported in one compound heterozygous proband (PMID: 25728920) with Pathogenic variant NM_000212.2:c.505C>T Arg169Ter (PM3_supporting). The patient (GT7 in PMID: 25728920/Case 2 in PMID: 35286390) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 15% (<25%), as measured by flow cytometry (PP4_strong). It occurs at an extremely low frequency, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population; PM2_supporting). It is predicted damaging by in-silico tools (REVEL score of 0.98; PP3). In transiently transfected COS‐7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of αIIbβ3Cys63 expression (PS3_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3, PS3_moderate (VCEP specifications version 2).

#	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

Last Updated: Jun 23, 2024

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