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]

Variant: NM_000419.5(ITGA2B):c.3092_3093dup (p.Glu1032fs)

CA500260678

953020 (ClinVar)

Gene: ITGA2B
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 9eb9a6cb-8091-4194-acd4-7baacc151f69
Approved on: 2023-06-01
Published on: 2023-06-02

HGVS expressions

NM_000419.5:c.3092_3093dup
NM_000419.5(ITGA2B):c.3092_3093dup (p.Glu1032fs)
NC_000017.11:g.44372391_44372392dup
CM000679.2:g.44372391_44372392dup
NC_000017.10:g.42449759_42449760dup
CM000679.1:g.42449759_42449760dup
NC_000017.9:g.39805285_39805286dup
NG_008331.1:g.22114_22115dup
ENST00000262407.6:c.3092_3093dup
ENST00000648408.1:n.2406_2407dup
ENST00000262407.5:c.3092_3093dup
ENST00000587295.5:n.285_286dup
ENST00000588098.1:n.69_70dup
NM_000419.3:c.3092_3093dup
NM_000419.4:c.3092_3093dup
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Uncertain Significance

Met criteria codes 3
PM2_Supporting PM4 PM3_Supporting
Not Met criteria codes 1
PP4

Evidence Links 1

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.3092_3093dup variant results in a frameshift, p.Glu1032TrpfsTer98, and introduction of a stop codon further than the original. This adds 90 amino acids to the ITGA2B protein. The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). It is reported in a compound heterozygous individual with the c.3060+2T>C variant (classified Pathogenic by the PD VCEP; PM3_supporting); however, the individual does not meet criteria for PP4 (PMID: 9215749). 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: PM2_Supporting, BP4 (PD VCEP specifications version 2.1).
Met criteria codes
PM2_Supporting
The c.3092_3093dup variant is absent from gnomAD and other databases.
PM4
The c.3092_3093dup variant causes a frameshift and subsequent stop loss, Glu1032TrpfsTer98. This results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain.
PM3_Supporting
This variant is found in trans (phase not confirmed) with the c.3060+2T>C variant (PMID: 9215749), classified as Pathogenic by the ClinGen Platelet Disorders VCEP. Therefore, 0.5 points is applied here for a pathogenic variant not confirmed in trans.
Not Met criteria codes
PP4
Patient MC from PMID: 9215749 does not meet criteria for PP4 due to absence of aggregometry information.
Patient MC is reported to have gingival bleeding, αIIbβ3 surface expression level of <12% and fibrinogen ~12%. Platelet count and aggregometry information is not available. Variant in trans: c.3060+2T>C (curated by Platelet Disorders VCEP to be likely pathogenic). PubMed:9215749
Curation History
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