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

Variant: NM_000419.3(ITGA2B):c.1787T>C


2900 (ClinVar)

Gene: ITGA2B
Condition: Glanzmann's thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: c6b42f33-92f7-4a71-822b-932469bd66ae

HGVS expressions


Uncertain Significance

Met criteria codes 2
PP4_Strong PP1
Not Met criteria codes 2

Evidence Links 4

Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000419.3:c.1787T>C that results in the Ile596Thr missense change is reported in at least 2 homozygous individuals with Glanzmann Thrombasthenia (PMIDs: 9734640, 22513797). It was found to co-segregate with disease in 1 additional family member. It is reported in gonmAD (v3 and v2.1.1 combined) at a frequency >0.0001. In summary, there is insufficient evidence at this time to classify the Ile596Thr variant. GT-specific codes applied: PP4_Strong, PP1.
Met criteria codes
Proband from PMID: 22513797 meet criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3.

Patient 3 is the 16yo sister of the proband, Patient 4. Both siblings are diagnosed with GT, homozygous for the variant and meet phenotype criteria, thus meeting PP1

Not Met criteria codes
The variant has been observed in the homozygous state in at least 2 apparently unrelated individuals (PMID: 22513797, 20020534) and in the compound heterozygous state in 2 individuals (PMID: 9215749, 9734640). PM3 is not applied as the variant does not meet PM2.
In-silico evidence is available from PMID: 29385657: the authors suggest that Ile596 is a likely mutational hot spot; it is relatively well conserved both between species and within human α‐subunits. They report that the Thr introduces an ‐OH alcoholic function close to Arg551, which competes for H‐bonds with residues Asp542, Ser594 and Asp591 changing interatom distances and creating an additional H‐bond within connecting loops extending from the lower region of the thigh. However, the Ile596Thr variant has a REVEL score <0.7: 0.628.
Approved on: 2020-09-06
Published on: 2021-01-28
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