NM_000212.3(ITGB3):c.718C>T (p.Arg240Trp) AND Glanzmann thrombasthenia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 20, 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:: RCV001580253.3

Allele description [Variation Report for NM_000212.3(ITGB3):c.718C>T (p.Arg240Trp)]

NM_000212.3(ITGB3):c.718C>T (p.Arg240Trp)

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.718C>T (p.Arg240Trp)

Other names:

R214W

HGVS:

NC_000017.11:g.47286363C>T
NG_008332.2:g.37522C>T
NM_000212.3:c.718C>TMANE SELECT
NP_000203.2:p.Arg240Trp
LRG_481:g.37522C>T
NC_000017.10:g.45363729C>T
NC_000017.10:g.45363729C>T
NM_000212.2(ITGB3):c.718C>T
NM_000212.2:c.718C>T
P05106:p.Arg240Trp

Protein change:

R240W; ARG214TRP

Links:

UniProtKB: P05106#VAR_004000; OMIM: 173470.0003; dbSNP: rs121918446

NCBI 1000 Genomes Browser:

rs121918446

Molecular consequence:

NM_000212.3:c.718C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001809897	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen Platelet ACMG Specifications v2-1)	Likely Pathogenic (Aug 20, 2024)	germline	curation	Citation Link,
SCV004848913	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001809897

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2-1)

Likely Pathogenic
(Aug 20, 2024)

germline

curation

Citation Link,

SCV004848913

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2023)

germline

clinical testing

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV001809897.2

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

Description

The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID: 32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848913.1

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

Description

The p.Arg240Trp variant in ITGB3 has been reported in 3 homozygous individuals with Glanzmann thrombasthenia (Lanza 1992 PMID: 1602006, Paciullo 2021 PMID: 32200672, Djaffar 1993 PMID: 7509233). It was also identified 0.001% (1/68038) of European chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org). The variant is also reported in ClinVar, and has been classified as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel (Variation ID 13555). In vitro analysis using patient derived platelets support an impact to normal protein function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant involving this codon (p.Arg240Gln) has been identified in individuals with Glanzmann thrombasthenia and is classified as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia. ACMG/AMP criteria applied: PM3, PM5, PS3_Supporting, PM2_Supporting, PP3, PP4.

#	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: Oct 13, 2024

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