Variant: NM_000212.3(ITGB3):c.355C>T (p.Arg119Trp)

CA8622924

812735 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: cb5cccf2-e599-48d8-b437-2b65b1a22be8

HGVS expressions

NM_000212.3:c.355C>T
NM_000212.3(ITGB3):c.355C>T (p.Arg119Trp)
NC_000017.11:g.47283543C>T
CM000679.2:g.47283543C>T
NC_000017.10:g.45360909C>T
CM000679.1:g.45360909C>T
NC_000017.9:g.42715908C>T
NG_008332.2:g.34702C>T
ENST00000559488.7:c.355C>T
ENST00000559488.5:c.355C>T
ENST00000560629.1:c.320C>T
ENST00000571680.1:c.355C>T
NM_000212.2:c.355C>T

Uncertain Significance

• Met criteria codes: PP3 PP4_Strong

• Not Met criteria codes: PM2 PM5 PM3

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3(ITGB3):c.355C>T variant predicts a missense change, Arg119Trp. It is reported at a low frequency of 0.00004454 (2/44902 alleles) in the East Asian population in gnomAD v4.0.0 however a homozygous individual is also present. At least 3 GT patients (compound heterozygous) with the variant have been reported in the literature (PMID: 12083483 and PMID: 32581362). Those from PMID: 12083483 meet criteria for PP4_Strong including bleeding phenotype, abnormal platelet aggregation in response to >2 agonists and normal aggregation to ristocetin, reduced αIIbβ3 integrin expression on flow cytometry and full sequencing of ITGA2B and ITGB3 both genes. The variant has a REVEL score of 0.883, meeting criteria for PP3 (threshold: >0.7). Another variant, Arg119Gln, evaluated as a VUS by the Platelet Disorders VCEP, has been reported at the same residue. In summary, there is insufficient evidence at this time to classify the Arg119Trp variant. GT-specific criteria met: PP3, PP4_strong.

Met criteria codes

• PP3: REVEL score for Arg119Trp is 0.883 and meets criteria for PP3 (threshold: >0.7)
• PP4_Strong: 2 probands from PMID: 12083483 meet criteria fro PP4_Strong including bleeding phenotype, abnormal platelet aggregation in response to >2 agonists and normal aggregation to ristocetin, reduced αIIbβ3 integrin expression on flow cytometry and full sequencing of ITGA2B and ITGB3 both genes.

Not Met criteria codes

• PM2: The variant is reported at a frequency of 0.00004454 (2/44902 alleles) in the East Asian population in gnomAD v4.0.0. meeting the PM2_supporthing threshold of <0.0001. However one homozygote is present so PM2 is not applied.
• PM5: Arg119Gln (c.356G>A) is a missense variant at the same residue. This variant is evaluated by the Platelet Disorders VCEP as a VUS. PM5 is not applicable at this time.
• PM3: At least 3 compound heterozygous probands have been reported with this variant in PMID: 12083483 and PMID: 32581362. PM3 is not applied because PM2_Supporting is not met.

Approved on: 2023-11-02

Published on: 2023-11-03