Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

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

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

ENST00000559488.7:c.718C>T

ENST00000559488.5:c.718C>T

ENST00000560629.1:n.683C>T

ENST00000571680.1:c.718C>T

NM_000212.3:c.718C>T

Likely Pathogenic

PP4_Moderate PP3 PM5 PM3 PM2_Supporting

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

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. It is occurs at a very low allele frequency of 0.00005437 (1/18,394 alleles) in the gnomAD East Asian population. It is predicted to have a deleterious effect (REVEL score 0.832) and occurs at the same residue as pathogenic variant Arg240Gln. 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.

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 an overall allele frequency from gnomAD of 0.00001205 and MAF of 0.00005437 (1/18,394 alleles) in the East Asian population.

Approved on: 2021-07-08

Published on: 2021-08-19

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