Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000419.5(ITGA2B):c.3076C>T (p.Arg1026Trp)

CA10575573

50233 (ClinVar)

Gene: ITGA2B
Condition: Glanzmann's thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 4624a88f-7844-4bac-87af-de25d8e9d74a

HGVS expressions

NM_000419.5:c.3076C>T
NM_000419.5(ITGA2B):c.3076C>T (p.Arg1026Trp)
NM_000419.3:c.3076C>T
NM_000419.4:c.3076C>T
ENST00000262407.5:c.3076C>T
ENST00000587295.5:n.269C>T
ENST00000588098.1:n.53C>T
NC_000017.11:g.44372408G>A
CM000679.2:g.44372408G>A
NC_000017.10:g.42449776G>A
CM000679.1:g.42449776G>A
NC_000017.9:g.39805302G>A
NG_008331.1:g.22098C>T

Uncertain Significance

Met criteria codes 2
PM2_Supporting PP3
Not Met criteria codes 3
PP4 PS3 PM5

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000419.5:c.3076C>T variant results in the Arg1026Trp missense change. It is absent in population databases and is predicted damaging by in silico tools (REVEL score of 0.897). All the individuals with this variant, reported in the literature, are heterozygous and have macrothrombocytopenia with or without a mild bleeding tendency (PMID: 31119735, 21454453, 31064749). In summary, there is insufficient evidence at this time to classify the Arg1026Trp variant. GT-specific criteria applied: PM2_Supporting, PP3.
Met criteria codes
PM2_Supporting
The variant is absent from population databases including gnomAD v2.1.1 and gnomAD v3 and meets criteria for PM2.
PP3
Arg1026Trp has a REVEL score of 0.897 and meets criteria for PP3 (REVEL >0.7)
Not Met criteria codes
PP4
All patients reported in the literature with the Arg1026Trp variant are heterozygous with no second mutation. Their phenotype is consistent with autosomal dominant macrothrombocytopenia and not GT.
PubMed:31119735
PubMed:21454453
PubMed:31064749
PS3
Experiments with the Arg1026Trp variant in 293T and CHO cells show that the variant causes constitutive activation of the mutant receptor. This evidence does not meet criteria for PS3.
αIIb-Trp1026 and wild-type β3 expressed in 293T cells revealed that the mutant αIIbβ3 complex spontaneously bound PAC-1. The mutant receptor is noted to be in the constitutively active conformation with spontaneous FAK phosphorylation. CHO cells transfected with αIIb-Trp1026 and wild-type β3 showed membrane ruffling and abnormal cytoplasmic protrusions with bulbous tips on fibrinogen-coated surfaces. PubMed:21454453
PM5
Arg1026Gln is a variant at the same residue, evaluated as a VUS in relation to Glanzmann's Thromasthenia by the Platelet Disorders VCEP.
Approved on: 2020-06-16
Published on: 2021-01-23
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