NM_000212.3:c.1801T>C

CA8623361

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 061617d0-1919-423b-80d3-0f65843148e7

Approved on: 2020-09-06

Published on: 2021-08-20

HGVS expressions

NM_000212.3:c.1801T>C
ENST00000559488.7:c.1801T>C
ENST00000559488.5:c.1801T>C
ENST00000560629.1:n.1766T>C
NM_000212.2:c.1801T>C
NC_000017.11:g.47299418T>C
CM000679.2:g.47299418T>C
NC_000017.10:g.45376784T>C
CM000679.1:g.45376784T>C
NC_000017.9:g.42731783T>C
NG_008332.2:g.50577T>C

Pathogenic

• Met criteria codes: PP1_Moderate PM2_Supporting PP3 PP4_Strong PM3

• Not Met criteria codes: PM5

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3:c.1801T>C variant in the ITGB3 gene predicts the missense change, Cys601Arg. This variant is absent from gnomAD v2.1.1 and v3 and meets criteria for PM2. It is reported in at least 4 GT patients (2 homozygous and 2 compound heterozygous), meeting the GT phenotype criteria (PMID: 12083483 and 25728920). Two additional family members who also showed the GT phenotype were found to be homozygous for this variant. The REVEL score for this variant is high (0.986), meeting PP3. The variant occurs at the same residue at which another missense variant, Cys601Gly has also been reported. In summary, this variant meets criteria to be classified as pathogenic. GT-specific criteria met: PM2_Supporting, PM3, PP1_Moderate, PP4_Strong, PP3.

Met criteria codes

• PP1_Moderate: 2 siblings (dizygotic twins) of proband CG in PMID: 12083483 are also homozygous for Cys601Arg. Criteria for PP4_Moderate met.
• PM2_Supporting: Cys601Arg is reported at a frequency of 0.00001758 (2/113754 alleles) in the non-Finnish European population in gnomAD v2.1.1 and meets criteria for PM2_Supporting (MAF <0.0001)
• PP3: REVEL score of 0.986 meets criteria for PP3 (threshold >0.7)
• PP4_Strong: At least 4 GT patients from PMID: 12083483 and 25728920 meet criteria for PP4_Strong including mucocutaneous bleeding, absent aggregation to >2 agonists, but normal response to ristocetin, <25% expression of αIIbβ3 by flow cytometry and/or WB. Both ITGA2B and ITGB3 were sequenced.
• PM3: 2 homozygous probands from PMID: 12083483 and 25728920 meet criteria for PM3.

Not Met criteria codes

• PM5: Cys601Gly is a variant reported at the same residue. PM5 is not considered in this instance to avoid circularity.