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]
  • No ClinVar Id was directly found from the curated document

Variant: NM_000419.5:c.3061-1G>A

CA399787972

Gene: ITGA2B
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: c266c29a-548a-4279-913f-2f50beec1f0d
Approved on: 2022-08-05
Published on: 2022-12-07

HGVS expressions

NM_000419.5:c.3061-1G>A
NC_000017.11:g.44372424C>T
CM000679.2:g.44372424C>T
NC_000017.10:g.42449792C>T
CM000679.1:g.42449792C>T
NC_000017.9:g.39805318C>T
NG_008331.1:g.22082G>A
ENST00000262407.6:c.3061-1G>A
ENST00000648408.1:n.2375-1G>A
ENST00000262407.5:c.3061-1G>A
ENST00000587295.5:n.254-1G>A
ENST00000588098.1:n.38-1G>A
NM_000419.3:c.3061-1G>A
NM_000419.4:c.3061-1G>A
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Pathogenic

Met criteria codes 4
PVS1_Strong PP4_Strong PM2_Supporting PM3_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000419.5(ITGA2B):c.3061-1G>A occurs within the canonical splice acceptor site of intron 29. It is predicted to cause skipping of biologically-relevant-exon 29, resulting in the in-frame deletion of 39 amino acids (3.7% of the protein) of the transmembrane region, which is considered a critical region by the PD-EP (PVS1_strong). At least one patient (GT31 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). GT31 is compound heterozygous for c.1771dup (classified Pathogenic by the PD-EP) and c.3061-1G>A (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1).
Met criteria codes
PVS1_Strong
The NM_000419.5:c.3061-1G>A occurs within the canonical splice acceptor site of intron 29. It is predicted to cause skipping of biologically-relevant-exon 29, resulting in the in-frame deletion of 39 amino acids (3.7% of the protein) of the transmembrane region, which is considered a critical region by the PD-EP (PVS1_strong).
PP4_Strong
At least one patient (GT31 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong)
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PM3_Supporting
GT31 (PMID: 25728920) is compound heterozygous for c.1771dup (classified Pathogenic by the PD-EP) and c.3061-1G>A. Confirmation of trans phase was not reported. (0.5pt; PM3_supporting)
Curation History
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