Variant: NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu)

CA8622980

696041 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 07604c9f-b616-435a-adca-38185c0f1c88

Approved on: 2023-02-08

Published on: 2023-02-15

HGVS expressions

NM_000212.3:c.557C>T
NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu)
NC_000017.11:g.47284638C>T
CM000679.2:g.47284638C>T
NC_000017.10:g.45362004C>T
CM000679.1:g.45362004C>T
NC_000017.9:g.42717003C>T
NG_008332.2:g.35797C>T
ENST00000559488.7:c.557C>T
ENST00000559488.5:c.557C>T
ENST00000560629.1:n.522C>T
ENST00000571680.1:c.557C>T
NM_000212.2:c.557C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence, Benign"

• Met criteria codes: BA1 PP3

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 c.557C>T variant in ITGB3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 186. The variant has a high population minor allele frequency in gnomAD v2.1.1 of 0.007131 (178/24960) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024). The computational predictor REVEL gives a score of 0.733, which is above the ClinGen PD VCEP PP3 threshold of >0.7 and predicts a damaging effect on ITGB3 function. It is reported to have an association with lower platelet count in an African American cohorts (PMID: 23103231) but has not been reported in a Glanzmann thrombasthenia patient to our knowledge. In summary, this variant meets the criteria to be classified as a variant of unknown significance - conflicting evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, PP3. (VCEP specifications version 2; date of approval 2/2/2023)

Met criteria codes

• BA1: The highest population minor allele frequency in gnomAD v2.1.1 is 0.007131 (178/24960) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1).
• PP3: The computational predictor REVEL gives a score of .733, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).