Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp)

CA123228

13555 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: bf7df2fe-141e-481a-befc-3d870f5eab47
Approved on: 2024-08-20
Published on: 2024-08-20

HGVS expressions

NM_000212.2:c.718C>T
NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp)
NC_000017.11:g.47286363C>T
CM000679.2:g.47286363C>T
NC_000017.10:g.45363729C>T
CM000679.1:g.45363729C>T
NC_000017.9:g.42718728C>T
NG_008332.2:g.37522C>T
ENST00000696963.1:c.718C>T
ENST00000559488.7:c.718C>T
ENST00000559488.5:c.718C>T
ENST00000560629.1:c.683C>T
ENST00000571680.1:c.718C>T
NM_000212.3:c.718C>T
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Likely Pathogenic

Met criteria codes 5
PP4_Moderate PP3 PM5 PM3 PM2_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
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.
Met criteria codes
PP4_Moderate
Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 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. Not reported if both ITGA2B and ITGB3 were fully sequenced in any of the patients.
PP3
The REVEL score for this variant is 0.832, exceeding the VCEP-established threshold of >0.7 to support a deleterious effect.
PM5
Arg240Trp occurs at the same residue as Arg240Gln (classified Pathogenic by the PD-VCEP).
PM3
Three probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous for Arg240Trp. A compound heterozygote has also been reported in https://doi.org/10.2491/jjsth.10.243 but is not considered here.
PM2_Supporting
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.
Curation History
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