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Variant: NM_000212.2(ITGB3):c.856G>C (p.Gly286Arg)

CA400024919

627151 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: 183a5591-df94-4c12-9ca7-29615d9ff1eb
Approved on: 2022-08-05
Published on: 2022-12-07

HGVS expressions

NM_000212.2:c.856G>C
NM_000212.2(ITGB3):c.856G>C (p.Gly286Arg)
NC_000017.11:g.47287148G>C
CM000679.2:g.47287148G>C
NC_000017.10:g.45364514G>C
CM000679.1:g.45364514G>C
NC_000017.9:g.42719513G>C
NG_008332.2:g.38307G>C
ENST00000559488.7:c.856G>C
ENST00000559488.5:c.856G>C
ENST00000560629.1:n.821G>C
ENST00000571680.1:c.856G>C
NM_000212.3:c.856G>C
NM_000212.3(ITGB3):c.856G>C (p.Gly286Arg)
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Uncertain Significance

Met criteria codes 3
PP3 PM2_Supporting PS1_Moderate
Not Met criteria codes 2
PM3 PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000212.3(ITGB3):c.856G>C (p.Gly286Arg) missense variant has been reported in at least one homozygous patient with abnormal bleeding (PMID: 31064749). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969 (PP3). The same amino acid change, resulting from a different nucleotide change c.856G>A, has been reported in a patient with Glanzmann thrombasthenia (PMIDs: 32237906, 21113249) and classified as Likely Pathogenic (PS1_moderate). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS1_moderate, PM2_supporitng, PP3. (VCEP specifications version 2; date of approval 08/04/2022).
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.969, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on ITGB3 function (PP3).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PS1_Moderate
The same amino acid change, resulting from a different nucleotide change c.856G>A, has been reported in a patient with Glanzmann thrombasthenia (PMIDs: 32237906, 21113249). The other variant has been classified as likely pathogenic by the ClinGen PD VCEP, thus PS1 has been applied at the moderate strength.
Not Met criteria codes
PM3
TGP0393, of PMID: 31064749, is homozygous for Gly286Arg. However, it is unclear that the patient's reported "disease of platelet function" is GT.
PP4
TGP0393 of PMID: 31064749 is stated to have a disease of platelet function, submitted in ClinVar as "abnormal bleeding." Communication with authors confirmed that the patient presented with bleeding and easy bruising. Platelet count 69x10^9/L. APTT + PT normal. Does not meet criteria for a highly specific phenotype of GT.
Curation History
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